CN1031376A - Pyrazolopyridine compound and preparation method thereof - Google Patents
Pyrazolopyridine compound and preparation method thereof Download PDFInfo
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- CN1031376A CN1031376A CN88104322A CN88104322A CN1031376A CN 1031376 A CN1031376 A CN 1031376A CN 88104322 A CN88104322 A CN 88104322A CN 88104322 A CN88104322 A CN 88104322A CN 1031376 A CN1031376 A CN 1031376A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
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Abstract
The present invention relates to Pyrazolopyridine compound and its salt of following formula, with and preparation method thereof.This compound can be used as diuretic(s) effectively, hypotensive agent, and treatment is suffered from a deficiency of the kidney and thrombotic medicine and cardiotonic drug, and this compound is:
R in the formula
1, R
2And R
3Definition is as specification sheets.
Description
The invention relates to new Pyrazolopyridine compound and its pharmacy acceptable salt.
The present invention particularly about those can be used as diuretic(s), hypotensive agent effectively, treatment is suffered from a deficiency of the kidney and the new Pyrazolopyridine compound of thrombotic medicine and cardiotonic drug and its pharmacy acceptable salt.The present invention is also about the preparation of this compound, and contains the pharmaceutical composition of this compound, also relates to the method for using this compound to cure the disease as the human and animal.
Therefore, an object of the present invention is to provide new Pyrazolopyridine compound and pharmacy acceptable salt thereof, they are used as diuretic(s), hypotensive agent effectively, treatment is suffered from a deficiency of the kidney and thrombotic medicine and cardiotonic drug.
Another object of the present invention provides the new Pyrazolopyridine compound of preparation and the method for salt thereof.
Further purpose of the present invention provides and contains above-mentioned Pyrazolopyridine compound or its pharmacy acceptable salt, as the pharmaceutical composition of active ingredient.
A further object of the invention provides a kind of this Pyrazolopyridine compound of use and suffers from a deficiency of the kidney and the thrombosis medicine as diuretic(s), hypotensive agent, treatment, and the method for cardiotonic drug, and it comprises this Pyrazolopyridine compound is administered to human body or animal body.
New Pyrazolopyridine compound of the present invention can be used following structural (I) expression:
Wherein: R
1Be low-carbon alkyl, can have one or more suitable substituent aryl or heterocyclic group,
R
2Be the following group of structural formula:
(R wherein
4Be amino or the hydroxyl of having protected,
R
5Be hydrogen or low-carbon alkyl);
Cyano group;
The group that structural formula is following:
(R wherein
6Be that acyl group, A can have one or more suitable substituent low-carbon (LC) aliphatic hydrocarbon groups);
Amidation carboxyl;
Amino or protected amino;
R
3Be hydrogen, low-carbon alkyl, low-carbon alkoxy or halogen.
Purpose compound of the present invention (I) and salt thereof can be by following reaction by way of preparations:
Method 1
Method 2
Method 5
Method 8
Method 11
Method 14
Method 17
Wherein: R
1, R
2, R
3, R
4, R
5, R
6Define as above with A,
R
1 aBe the aryl that has nitro,
R
1 bBe to have amino aryl,
R
1 cBe the aryl that has the amino of having protected,
R
2 aThe carboxyl that is amidation,
R
2 bThe amino that is amino or has protected,
R
2 cBe the amino of having protected
R
6 aBe the carboxyl of having protected,
R
6 bThe carboxyl that is amidation,
R
7Be the lower alkanes acyl group,
R
8Be esterifying carboxyl group,
R
1 NBe have hydroxyl (low-carbon (LC)) alkyl contain the N heterocyclic group,
R
2 NBe have low-carbon alkoxy (low-carbon (LC)) alkyl contain the N heterocyclic group,
R
3 NBe have acyloxy (low-carbon (LC)) alkyl contain the N heterocyclic group,
R
4 NBe have the carboxyl protected contain the N heterocyclic group,
R
5 NBe have a carboxyl contain the N heterocyclic group,
A
1Be to have one or more suitable substituent low carbon chain thiazolinyls,
A
1 aBe the low carbon chain thiazolinyl,
A
1 bBe the low carbon chain thiazolinyl that has halogen,
A
2Be the low-carbon (LC) alkynyl,
X is a leavings group.
About initial compounds, (I is new with (I x) v) to some compounds, can be according to disclosed method or similar approach preparation among the preparation method 1 and 2 of following introduction.
The pharmacy acceptable salt that is suitable for of purpose compound (I) is some conventional salt, comprises metal-salt, as an alkali metal salt (for example sodium salt, sylvite etc.); And alkaline earth salt (calcium salt for example, magnesium salts etc.), ammonium salt, organic alkali salt (trismethylamine salt for example, triethyl amine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt, N, N '-diphenyl-methyl ethylene diamine salt etc.), organic acid salt (acetate for example, trifluoroacetate, maleate, Tartaric acid salt, fumarate, mesylate, benzene sulfonate, cresylate, tosylate etc.), inorganic acid salt (hydrochloride for example, hydrobromate, hydriodate, vitriol, phosphoric acid salt etc.), have amino acid whose salt (arginine for example, aspartic acid, L-glutamic acid etc.) etc.
In the description of this context, suitable embodiment and will do detailed explanation hereinafter to the explanation of the various definition that are included in the scope of the present invention.
Term " low-carbon (LC) " except that particularly pointing out, is meant 1～6 carbon atom.
Term " high-carbon " except that particularly pointing out, is meant 7～20 carbon atoms.
Suitable " low-carbon (LC) aliphatic hydrocarbon group " can comprise the low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl of description below etc.
Suitable " low-carbon alkyl " can comprise the straight or branched alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl etc., wherein C
1～C
4Alkyl is preferable, more preferably methyl, ethyl, propyl group and sec.-propyl.
Suitable " low carbon chain thiazolinyl " can comprise the straight or branched thiazolinyl, for example vinyl, 1-methyl ethylene, 2-methyl ethylene, 1-propenyl, 2-propenyl, 1-butylene base, 2-methyl isophthalic acid-propenyl, 1,3-butadienyl, 1-pentenyl, 4-pentenyl, 1-hexenyl, 1,4-hexadienyl, 5-hexenyl etc., wherein (C
2～C
4) alkenyl is preferable, more preferably vinyl, 1-methyl ethylene, 2-methyl ethylene and 1,3-butadiene base.
Suitable " low-carbon (LC) alkynyl " can comprise the straight or branched alkynyl, for example ethynyl, 1-proyl, 1-methyl-ethynyl, 2-butyne base, 2-methyl-3-butynyl, valerylene base, 1-hexin base etc., wherein C
2～C
4Alkynyl is preferable, and best is ethynyl.
Above-mentioned " low-carbon (LC) aliphatic hydrocarbon group " can have one or more (best 1～3) suitable substituents, for example halogen (as chlorine, bromine, fluorine, iodine) etc.
Suitable " protect amino " can comprise the amino that amido protecting group with routine has replaced; low-carbon alkyl amino (as methylamino, ethylamino, propyl group amino, butyl amino, tertiary butyl amino, amyl group amino, hexyl amino etc.) for example; two (low-carbon (LC)) alkylamino, (for example dimethylamino, diethylamino, N-ethyl propyl amino, dibutylamino, the N-(tertiary butyl) amyl group amino, dihexyl amino etc.), the amido of description below etc.
Suitable " amido " can comprise urea groups; Lower alkanes amido (formamido group for example, kharophen, propionamido, butyrylamino, isobutyryl amino, trimethyl-acetyl, hexanamido etc.), low-carbon alkoxy carbonylamino (methoxycarbonyl amino for example, ethoxy carbonyl amino, propoxycarbonyl amino, tert-butoxycarbonyl amino, pentyloxy carbonyl amino, hexyloxy carbonyl amino etc.), low-carbon alkoxy carbonyl (low-carbon (LC)) alkanoyl amido (methoxycarbonyl kharophen for example, the ethoxy carbonyl kharophen, the 2-(propoxycarbonyl)-propionamido, the 4-(tert-butoxycarbonyl) butyrylamino, the 2-(butoxy carbonyl methyl) propionamido, 2-methyl-2-(pentyloxy carbonyl methyl) propionamido, 6-hexyloxy carbonyl-hexanamido etc.), lower alkanes sulfonamido (sulfonyl methane amino for example, the ethane sulfonamido, the propane sulfonamido, the butane sulfonamido, uncle's butane sulfonamido, the pentane sulfonamido, hexane sulfonamido etc.) etc.
Above-mentioned " lower alkanes amido " can have suitable substituting group, for example two (low-carbon (LC)) alkylamino (as dimethylamino, N-methyl-N-ethylamino, dipropyl amino, di-t-butyl amino, N-amyl group-N-hexyl amino etc.); Can have ring amino (as piperidino-(1-position only) etc.) of low-carbon alkyl etc.; The suitable example of above-mentioned " having suitable substituent lower alkanes amido " comprising: lower alkanes amido (the dimethylamino carbonylamino for example that has two (low-carbon (LC)) alkylamino, 2-dimethylamino kharophen, 2-(N-methyl-N-ethylamino) kharophen, 2-dimethylamino-propionamido, the amino butyrylamino of 3-dipropyl, 2-(two-tertiary butyl amino)-2-methyl-prop amido, 2-dimethylaminomethyl-2-methyl-prop amido, 6-(N-amyl group-N-hexyl amino) hexanamido etc.);
Lower alkanes amido (for example piperidino-(1-position only) carbonylamino, 2-piperidino-(1-position only) kharophen, the 2-(2-methyl piperidine subbase) kharophen, the 2-(2-ethyl piperidine subbase that have the ring amino that can contain low-carbon alkyl) kharophen, 2-piperidino-(1-position only) propionamido, 3-(2-ethyl piperidine subbase) butyrylamino, 2-(4-ethyl-piperidino-(1-position only)-2-methyl-prop amido, 2-piperidino-(1-position only) methyl-2-methyl-prop amido, 6-(3-propyl group piperidino-(1-position only)) hexanamido etc.), etc.
In above-mentioned " amido ", preferably urea groups, (C
1～C
4) alkanoyl amido, (C
1～C
4) alkoxy carbonyl (C
1～C
4)-alkanoyl amido, two (C
1～C
4) alkylamino (C
1～C
4) alkanoyl amido, (C
1～C
4) Alkylpiperidine subbase (C
1～C
4) alkanoyl amido, (C
1～C
4) alkoxycarbonyl amino, (C
1～C
4) alkane sulfonamido, (C
1～C
4) alkylamino and two (C
1～C
4) alkylamino, wherein best is urea groups, kharophen, 2-(ethoxy carbonyl) kharophen, 2-dimethylamino kharophen, 2-(2-ethyl piperidine subbase) kharophen, methoxycarbonyl amino, sulfonyl methane amino, methylamino and dimethylamino.
Suitable " carboxyl groups " can comprise lower alkanes acyl group (as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pivaloyl, caproyl etc.); Carboxyl; Carboxyl of having protected etc.
The suitable example of above-mentioned " protect carboxyl " can be an esterifying carboxyl group, and wherein suitable esterifying carboxyl group can comprise low-carbon alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl etc.) that contains the N heterocyclic group having of description below etc.;
The amidation carboxyl, wherein suitable amidation carboxyl comprises the N-(low-carbon (LC)) alkyl-carbamoyl (for example N-methyl-formamyl, N-ethylamino formyl radical, N-sec.-propyl formamyl, N-butyl formamyl, N-amyl group formamyl, N-hexyl formamyl etc.);
The N-(high-carbon) alkyl-carbamoyl (for example N-amyl group formamyl, N-(2-methyl amyl) formamyl, N-nonyl formamyl, N-decyl formamyl, N-three rings (3,3,1,1
3.7)-decyl formamyl, N-+-alkyl-carbamoyl, N-(two rings (4,3,2)-+-alkyl) formamyl, N-dodecyl formamyl, N-tridecyl formamyl, N-tetradecyl formamyl, N-pentadecyl formamyl, N-hexadecyl formamyl, N-heptadecyl formamyl, N-octadecyl formamyl, N-nonadecyl formamyl, N-eicosyl formamyl etc.);
N; N-two (low-carbon (LC)) alkyl-carbamoyl (N for example; N-formyl-dimethylamino, N; N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, N; N-dipropyl formamyl, N, N-two (tertiary butyl)-formamyl, N-amyl group-N-hexyl formamyl etc.).
N-low-carbon alkyl-N-aryl (low-carbon (LC)) alkyl-carbamoyl (for example N-methyl-N-benzylamino formyl radical, etc.);
The group that structural formula is following:
-COR
N
R wherein
NBe to have the one or more suitably substituent N of containing heterocyclic groups, this contains N heterocycle R
NGroup can contain other heteroatoms, for example N, O or S on its ring.
Suitable " containing the N heterocyclic group " can comprise saturated or unsaturated, monocycle or encircle heterocyclic group more, for example undersaturated 3～8 members (being preferably 5～7 members) heterocyclic group that contains 1～4 nitrogen-atoms, for example: azepines base (for example 1H-azepines base etc.), pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide compound, the dihydropyridine base, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (4H-1 for example, 2, the 4-triazolyl, 1H-1,2, the 3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (1H-tetrazyl for example, 2H-tetrazyl etc.) etc.;
3～8 saturated members (preferably 5～7 members) heterocyclic group that contains 1～4 nitrogen-atoms, for example, perhydro azepines base (as perhydro-1H-azepines base etc.), pyrrolidyl, imidazolidyl, piperidino-(1-position only), piperazinyl etc.;
The unsaturated annelated heterocycles group that contains 1～4 nitrogen-atoms, for example indyl, pseudoindoyl, indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base etc.;
The saturated annelated heterocycles group that contains 1～4 nitrogen-atoms, for example 7-azabicyclo (2,2,1)-heptyl, 3-azabicyclo (3,2,2) nonyl etc.;
Unsaturated 3～8 members (preferably 5 or 6 members) heterocyclic group that contains 1～2 Sauerstoffatom and 1～3 nitrogen-atoms, example is as oxazolyl, isoxazolyl, oxadiazole base (as 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base etc.) etc.;
Saturated 3～8 members (preferably 5 or 6 members) heterocyclic group, for example morpholinyl, the sydnone base etc. that contain 1～2 Sauerstoffatom and 1～3 nitrogen-atoms;
The unsaturated annelated heterocycles group that contains 1～2 Sauerstoffatom and 1～3 nitrogen-atoms, for example benzoxazolyl, benzo oxadiazoles base etc.;
Unsaturated 3～8 members (preferably 5 or 6 members) heterocyclic group that contains 1～2 sulphur atom and 1～3 nitrogen-atoms, for example thiazolyl, isothiazolyl, thiadiazolyl group (for example 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.), dihydro thiazinyl etc.;
Saturated 3-8 member (preferably 5 or 6 members) heterocyclic group that contains 1～2 sulphur atom and 1～3 nitrogen-atoms, for example thiazolidyl etc.;
The unsaturated annelated heterocycles group that contains 1-2 sulphur atom and 1～3 nitrogen-atoms, for example benzothiazolyl, diazosulfide base etc.;
Wherein preferable group comprises saturated 3～8 element heterocycle groups that contain 1～4 nitrogen-atoms,
Contain 1～4 nitrogen-atoms saturated annelated heterocycles group and
Saturated 3～8 element heterocycle groups that contain 1～2 Sauerstoffatom and 1～3 nitrogen-atoms.
" nitrogen heterocyclic ring group " can have one or more suitable substituents thus defined, low-carbon alkyl for example above-mentioned; Hydroxyl (low-carbon (LC)) alkyl (for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 1-methyl isophthalic acid-hydroxymethyl ethyl, 4-hydroxyl amyl group, 3-hydroxyl hexyl etc.); Low-carbon alkoxy (low-carbon (LC)) alkyl (for example methoxymethyl, 2-methoxy ethyl, 1-ethoxyethyl group, 3-propoxy-propyl group, 2-(tert.-butoxy) butyl, 5-pentyloxy amyl group, 3-hexyloxy hexyl etc.); Acyloxy (low-carbon (LC)) alkyl, as lower alkanes acyloxy (low-carbon (LC)) alkyl (for example acetoxy-methyl, 1-acetoxyl group ethyl, 2-acetoxyl group ethyl, 2-propionyloxy ethyl, 3-propionyloxy propyl group, 2-butyryl acyloxy butyl, 4-trimethyl acetoxyl amyl group, 6-hexylyloxy hexyl etc.) etc.; The carboxyl low-carbon alkoxy carbonyl of having protected as mentioned above; Carboxyl etc.
In above-mentioned " can have suitably one or more the substituent N of containing heterocyclic groups ", be preferably and have 1～4 substituent piperidino-(1-position only) that is selected from following groups, these groups are:
(C
1～C
4) alkyl, hydroxyl (C
1～C
4) alkyl, (C
1～C
4) alkoxyl group-(C
1～C
4) alkyl, (C
1～C
4) alkanoyloxy (C
1～C
4) alkyl, (C
1～C
4) alkoxy carbonyl and carboxyl (piperidino-(1-position only) for example, 2-methyl-piperidino-(1-position only), 2-ethyl piperidine subbase, 3-ethyl piperidine subbase, 4-ethyl piperidine subbase, 2-propyl group piperidino-(1-position only), 4-sec.-propyl piperidino-(1-position only), 2-butyl piperidine subbase, the 3-(tertiary butyl) piperidino-(1-position only), 4-amyl piperidine subbase, 2-hexyl piperidino-(1-position only), 2,2,6,6-tetramethyl piperidine subbase, 2,2-dimethyl-6,6-diethyl piperidino-(1-position only), 2-hydroxymethyl piperidino-(1-position only), 3-hydroxymethyl piperidino-(1-position only), the 2-(1-hydroxyethyl) piperidino-(1-position only)), the 2-(2-hydroxyethyl) piperidino-(1-position only), the 3-(2-hydroxyethyl) piperidino-(1-position only), the 4-(2-hydroxyethyl) piperidino-(1-position only), the 2-(3-hydroxypropyl) piperidino-(1-position only), the 3-(2-hydroxybutyl) piperidino-(1-position only), 2-(1-methyl isophthalic acid-hydroxymethyl ethyl) piperidino-(1-position only), 4-(4-hydroxyl amyl group) piperidino-(1-position only), 2-(3-hydroxyl hexyl) piperidino-(1-position only), 2-methoxymethyl piperidino-(1-position only), the 2-(2-methoxy ethyl) piperidino-(1-position only), the 2-(1-ethoxyethyl group) piperidino-(1-position only), 3-(3-propoxy-propyl group) piperidino-(1-position only), 4-the 2-(tert.-butoxy) butyl }-piperidino-(1-position only), 2-(5-pentyloxy amyl group) piperidino-(1-position only), 3-(3-hexyloxy hexyl) piperidino-(1-position only), 2-acetoxy-methyl piperidino-(1-position only), 3-(1-acetoxyl group ethyl) piperidino-(1-position only), 2-(2-acetoxyl group ethyl) piperidino-(1-position only), 3-(2-propionyloxy ethyl) piperidino-(1-position only), 4-(3-propionyloxy propyl group) piperidino-(1-position only), 2-(2-butyryl acyloxy butyl) piperidino-(1-position only), 3-(4-trimethyl acetoxyl amyl group) piperidino-(1-position only), the own oxygen acyl group of 2-(6-hexyl) piperidino-(1-position only), 2-methoxycarbonyl piperidino-(1-position only), 2-ethoxy carbonyl piperidino-(1-position only), 2-propoxycarbonyl piperidino-(1-position only), 3-butoxy carbonyl piperidine subbase, the 4-(tert-butoxycarbonyl) piperidino-(1-position only), 2-pentyloxy carbonyl piperidino-(1-position only), 2-hexyloxy carbonyl piperidino-(1-position only), 2-carboxyl piperidino-(1-position only), 3-carboxyl piperidino-(1-position only), 4-carboxyl piperidino-(1-position only), the 2-(2-hydroxyethyl)-3-methyl piperidine subbase, the 2-(2-hydroxyethyl)-4-carboxyl piperidino-(1-position only) etc.);
Can have (C
1～C
4) alkoxyl group-(C
1～C
4) tetramethyleneimine-1-base (for example tetramethyleneimine-1-base, 2-methoxymethyl tetramethyleneimine-1-base, 2-(2-methoxy ethyl) tetramethyleneimine-1-base, the 2-(1-ethoxyethyl group of alkyl) tetramethyleneimine-1-base, 3-(3-propoxy-propyl group)-tetramethyleneimine-1-base, 3-{ 2-(tert.-butoxy) butyl } tetramethyleneimine-1-base, 2-(5-pentyloxy amyl group) tetramethyleneimine-1-base, 2-(3-hexyloxy hexyl) tetramethyleneimine-1-base etc.);
Perhydro azepines-1-base (for example perhydro-1H-azepines-1-base, etc.);
Can have (C
1～C
4) alkyl piperazine-1-base (for example piperazine-1-base, 2-methylpiperazine-1-base, 3-methylpiperazine-1-base, 4-methylpiperazine-1-base, 2-ethyl piperazidine-1-base, 3-propyl group piperazine-1-base, 4-sec.-propyl piperazine-1-base, 2-butyl piperazine-1-base, the 3-(tertiary butyl) piperazine-1-base, 4-amyl group piperazine-1-base, 4-hexyl piperazine-1-base, etc.);
Morpholino; 7-azabicyclo (2,2,1) heptan-7-base; 3-azabicyclo (3,2,2) ninth of the ten Heavenly Stems-3-base etc.;
Best is piperidino-(1-position only), the pipecoline subbase, 2-ethyl piperidine subbase, 3-ethyl piperidine subbase, 4-ethyl piperidine subbase, 2-propyl group piperidino-(1-position only), 2,2,6,6-tetramethyl piperidine subbase, 2-hydroxymethyl piperidino-(1-position only), the 2-(2-hydroxyethyl) piperidino-(1-position only), the 4-(2-hydroxyethyl) piperidino-(1-position only), 2-methoxymethyl piperidino-(1-position only), the 2-(2-methoxy ethyl) piperidino-(1-position only), 2-acetoxy-methyl piperidino-(1-position only), 2-(2-acetoxyl group ethyl) piperidino-(1-position only), 2-ethoxy carbonyl piperidino-(1-position only), 2-carbonyl piperidino-(1-position only), tetramethyleneimine-1-base, 2-methoxymethyl tetramethyleneimine-1-base, perhydro-1H-azepines-1-base, 4-methyl-piperazine-1-base, morpholino, 7-azabicyclo (2,2,1) heptan-the 7-base, 3-azabicyclo (3,2,2) ninth of the ten Heavenly Stems-3-base etc.
Suitable " N-replaces amine " can comprise low-carbon alkyl amine (for example methylamine, ethylamine, isopropylamine, butylamine, amylamine, hexyl amine etc.);
(for example heptyl amine, 2-methylheptyl amine, nonyl amine, decyl amine, three encircle (3,3,1,1 to the high-carbon alkylamine
3.7)-decyl amine, undecyl amine, dicyclo (4,3,2) undecyl amine, lauryl amine, tridecyl amine, tetradecylamine, pentadecyl amine, hexadecylamine, heptadecyl amine, octadecylamine, nonadecyl amine, eicosyl amine etc.);
Two (low-carbon (LC)) alkylamine (for example dimethyl amine, diethylamide, N-methylethyl amine, dipropylamine, two (tertiary butyl) amine, N-amyl group hexyl amine etc.);
N-low-carbon alkyl-aryl (low-carbon (LC)) alkylamine (for example N-methyl benzene methanamine etc.);
The compound that structural formula is following:
N-R
N
(R wherein
NDefinition as above)
Suitable " aryl " can comprise phenyl, naphthyl, indenyl, anthryl etc.; should " aryl " can have one or more suitable substituents, for example halogen atom (as fluorine, chlorine, bromine, iodine), low-carbon alkoxy (for example methoxyl group, oxyethyl group, propoxy-, tert.-butoxy, pentyloxy, hexyloxy etc.), nitro, amino, the foregoing amino of having protected etc.
The preferred example that " can have one or more suitable substituent aryl " comprising: can have 1～3 suitable substituent phenyl that is selected from following groups, these substituting groups are: halogen, (C
1～C
4) alkoxyl group, nitro, amino, (C
1～C
4) alkanoyl amino, (C
1～C
4) alkoxycarbonyl amino, (C
1～C
4) alkane sulfonamido, (C
1～C
4) alkylamino and two (C
1～C
4) alkylamino.In the above-mentioned preferred example preferably phenyl, chloride phenyl, contain methoxyl group phenyl, contain nitro phenyl, contain amino phenyl, contain kharophen phenyl, contain methoxycarbonyl amino phenyl, contain sulfonyl methane amino phenyl, contain the phenyl of methylamino and contain the phenyl of dimethylamino.
Suitable " heterocyclic group " can comprise the heterocyclic group that exemplifies above-mentioned in " nitrogen heterocyclic ring group ";
Unsaturated 3～8 members (preferably 5 or 6 members) heterocyclic group that contains a Sauerstoffatom, for example furyl etc.;
Unsaturated 3～8 members (preferably 5 or 6 members) heterocyclic group that contains a Sauerstoffatom and 1～2 sulphur atom, for example dihydro oxathiin base etc.;
The unsaturated annelated heterocycles group that contains 1～2 sulphur atom, for example benzothienyl, benzo dithia cyclohexadienyl, etc.;
The unsaturated annelated heterocycles group that contains a Sauerstoffatom and 1～2 sulphur atom, for example benzo oxathiin base etc.; Wherein preferably contain unsaturated 3～8 element heterocycle groups of 1～4 nitrogen-atoms, pyridyl is better, and is the best with 2-pyridyl, 3-pyridyl and 4-pyridyl.
Suitable " the low-carbon (LC) thiazolinyl that has halogen " can comprise that 1-is fluoride-based, 1-bromo vinyl, 1-chloro-2-methyl ethylene, 1-bromo-1-propenyl, 2-chloro-2-propenyl, 1-iodo-1-butylene base, 1-bromo-2-methyl isophthalic acid-propenyl, 3-bromo-1,3-butadiene base, 1-chloro-1-pentenyl, 4-chloro-4-pentenyl, 1-bromo-1-hexenyl etc.
Suitable " low-carbon alkoxy " can comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.
Suitable " halogen " can comprise fluorine, chlorine, bromine and iodine.
Suitable " leavings group " can comprise two (low-carbon (LC))-alkylaminos (for example dimethylamino, diethylamino, N-ethyl propyl amino, dibutylamino, N-amyl group hexyl amino etc.), low-carbon alkoxy above-mentioned, halogen above-mentioned, lower alkanes sulfenyl (for example methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl, own sulfenyl etc.) etc.
The preparation method of purpose compound of the present invention (I) elaborates below.
Method 1
By compound (II) or its salt and compound (III) or its salt are reacted, (I a) or its salt can to prepare the purpose compound.
(I a), the acceptable acid addition salts of (II) and (III) can be considered to the acid salt that exemplifies for compound (I) for compound.
This reaction is normally at conventional solvent, for example carries out in alcohol (as methyl alcohol, ethanol) or other solvent that this reaction is had no adverse effect.
This reaction is carried out under solutions of weak acidity usually.
Temperature of reaction is inessential, and reaction can be carried out under heating.
Method 2
By making compound (I b) or its salt carry out dehydration reaction, can prepare purpose compound (I c) or its salt.
The acceptable acid addition salts of compound (I b) and (I c) can be considered to the acid salt that exemplifies for compound (I).
The dehydration reaction of this method can be carried out according to usual manner, also can pass through compound (I b) or its salt and isocyanic acid low-carbon alkyl (for example isocyanic acid methyl ester etc.), in conventional solvent (for example methylene dichloride, chloroform etc.), under cooling, room temperature or heating condition, react.
Method 3
Uncommon reaction can prepare purpose compound (I d) or its salt through so-called dimension ladder to make compound (IV) or its salt.
The acceptable acid addition salts of compound (I d) can be considered to the compound that exemplifies for compound (I).
The acceptable acid addition salts of compound (IV) can be considered to the acid salt that exemplifies for compound (I).
The reaction of present method can be undertaken by the uncommon reagent react of dimension ladder that compound (IV) or its salt and following molecular formula are represented:
（R
9）
3-P＝A
3-R
6（Ⅹ）
(R wherein
9Be aryl or low-carbon alkyl, define as above respectively,
R
10Be the low-carbon alkyl as above mentioned,
R
6The definition as above,
A
3Be low-carbon (LC) alkylidene group (for example methylene radical, ethylidene, propylidene, 1-methyl-ethylidene, butylidene, 2-methyl propylidene, pentylidene etc.) or low-carbon (LC) alkenylene (for example vinylidene, 2-propenylidene, 2-crotonylidene, 4-inferior pentenyl etc.),
A
4Be low-carbon alkyl or low carbon chain thiazolinyl, respectively as mentioned above.〕
The uncommon reagent (X) of above-mentioned dimension ladder and (XI) can prepare according to general method.
Under the situation of using the uncommon reagent (XI) of dimension ladder, the reaction of present method can have alkali in the presence of carry out the alkali of use such as alkalimetal hydride (for example sodium hydride, potassium hydride KH etc.), basic metal low-carbon (LC) alkoxide (for example potassium tert.-butoxide etc.) etc.
Reaction is usually at conventional solvent, as Anaesthetie Ether, tetrahydrofuran (THF), methylene dichloride, benzene, toluene, N, carries out in dinethylformamide or any other solvent that reaction is had no adverse effect.
Temperature of reaction is inessential, and reaction can be carried out under cooling, room temperature, warm or heating.
Reaction conditions can determine according to the type of compound (IV) and the uncommon reagent of dimension ladder of use.
Method 4
Make compound (I e) or its salt carry out the elimination reaction of carboxyl-protecting group, can prepare purpose compound (I f) or its salt.
The acceptable acid addition salts of compound (I e) and (I f) is considered to the compound that exemplifies for compound (I).
Reaction is carried out according to conventional methods, as hydrolysis etc.
Hydrolysis preferably have alkali or acid (comprising Lewis acid) in the presence of carry out.Suitable alkali can comprise mineral alkali and organic bases, for example basic metal (as sodium, potassium etc.), alkaline-earth metal (as magnesium, calcium etc.), its oxyhydroxide or carbonate or supercarbonate, trialkylamine (for example Trimethylamine, triethylamine etc.), picoline, 1,5-diazabicyclo (4,3,0) ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo (2,2,2) octane, 1,8-diazabicyclo (5,4,0)-11-7-alkene etc.
Suitable acid can comprise organic acid (for example formic acid, acetate, propionic acid, trichoroacetic acid(TCA), trifluoroacetic acid etc.) and mineral acid (for example hydrochloric acid, Hydrogen bromide, sulfuric acid, hydrogenchloride, hydrogen bromide etc.).
Use Lewis acid, for example elimination reaction carried out of three halogen acetic acids (as trichoroacetic acid(TCA), trifluoroacetic acid etc.), preferably have positively charged ion absorption agent (for example methyl-phenoxide, phenol etc.) in the presence of carry out.
Reaction normally a solvent such as water, alcohol (for example methyl alcohol, ethanol etc.), methylene dichloride, tetrahydrofuran (THF), and composition thereof, or carry out in any other solvent that reaction is had no adverse effect, liquid base or acid also can be used as solvent.
Temperature of reaction is inessential, the reaction normally be cooled to the heating under carry out.
Method 5
By making compound (I f) or its at the reactive derivative on the carboxyl or its salt and N-replaces amine (V) or its reactive derivative or its salt on amino reacts, can prepare purpose compound (I g) or its salt.
The acceptable acid addition salts of compound (I f) and (I g) can be considered to the compound that exemplifies for compound (I).
The acceptable acid addition salts that N-replaces amine (V) can be considered to the compound that exemplifies for compound (I).
The suitable reactive derivative of compound (I f) on carboxyl comprises acyl halide, acid anhydrides, active amide, active ester etc.Suitable reactive derivative can be chloride of acid, acid azide, with a kind of mixed acid anhydride of acid, this acid is as the phosphoric acid (for example dialkyl group phosphoric acid, phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halophosphoric acid etc.) that replaces, dialkyl group phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (for example methanesulfonic etc.), aliphatic carboxylic acid (for example acetate, propionic acid, butyric acid, isopropylformic acid, trimethylacetic acid, valeric acid, isovaleric acid, 2 Ethylbutanoic acid, trichoroacetic acid(TCA) etc.) or aromatic carboxylic acid (for example phenylformic acid etc.); Symmetric anhydride; Active amide with imidazoles, 4-substituted imidazole, dimethyl pyrazole, triazole, tetrazolium or 1-hydroxyl-1H-benzotriazole; Or active ester (for example cyano methyl ester, methoxymethyl ester, dimethylimino methyl
Ester; vinyl ester; propargyl ester; right-the nitrophenyl ester; 2; 4-dinitrophenyl ester; the trichlorophenyl ester; the five chlorophenyl ester; the methylsulfonyl phenylester; the phenylazo-phenylester; the phenyl monothioester; right-the nitrophenyl monothioester; right-the cresyl monothioester; the carboxymethyl monothioester; the pyranyl ester; pyridyl ester; the piperidyl ester; 8-quinolyl monothioester etc.) or with N-oxy-compound (N for example; N-dimethyl hydroxyl amine; the 1-hydroxyl-2-(1H)-pyridone; N-hydroxyl-succinimide; the N-hydroxyphthalimide; 1-hydroxyl-1H-benzotriazole etc.) ester, or the like.According to the type of employed compound (I f), can therefrom select these reactive derivatives arbitrarily.
Suitable reactive derivative on the amino of N-replacement amine (V) can comprise that replacing amine (V) by N-reacts the schiff's base type imino-of formation or the enamine type isomer of its change with carbonyl compound (as aldehyde, ketone etc.); Replace amine (V) and silyl compound by N-, as two (trimethyl silyl) ethanamide ,-silyl derivative that reactions such as (trimethyl silyl) ethanamide, two (trimethyl silyl) urea form; Replace the derivative that amine (V) and phosphorus trichloride or phosgene reaction form by N-, or the like.
Reaction is normally at conventional solvent, for example water, alcohol (as methyl alcohol, ethanol etc.), acetone, diox, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N carry out in dinethylformamide, pyridine or any other organic solvent that reaction is had no adverse effect.These conventional solvents also can form mixture with water and use.
In this reaction, when compound (I f) used with free acid form or its salt form, reaction was preferably in conventional condensing agent, and for example N carries out under N '-existence such as dicyclohexyl carbodiimide.
Reaction can also have inorganic or organic bases in the presence of carry out, for example alkaline carbonate, alkali metal hydrocarbonate, three (low-carbon (LC))-alkylamine (for example triethylamine etc.), pyridine, N-(low-carbon (LC))-alkyl morpholine, N, N-two (low-carbon (LC)) alkyl benzyl amine etc.
Temperature of reaction is inessential, the reaction usually be cooled to the heating under carry out.
Method 6
By making compound (I h) or its salt carry out halogenating reaction, can prepare purpose compound (I i) or its salt.
The acceptable acid addition salts of compound (I h) and (I i) can be considered to the compound that exemplifies for compound (I).
This halogenating reaction can carry out according to usual manner, for example pass through compound (I h) or its salt and halogen (for example bromine, chlorine etc.) at conventional solvent, in any other solvent that has no adverse effect as methylene dichloride, chloroform or to reaction, under cooling or room temperature, react.
Method 7
By making compound (I i) or its salt carry out the elimination reaction of hydrogen halide, can prepare purpose compound (I j) or its salt.
The acceptable acid addition salts of compound (I i) and (I j) can be considered to the compound that exemplifies for compound (I).
This elimination reaction can be carried out according to usual manner, for example by making compound (I i) or its salt and alkali, for example alkali metal hydroxide (as sodium hydroxide, potassium hydroxide etc.), alkali metal alcoholates (for example sodium ethylate, potassium tert.-butoxide etc.), at conventional solvent, for example in chloroform, methyl alcohol, ethanol, the dimethyl sulfoxide (DMSO) etc., react under the heating being cooled to.
Method 8
By making compound (I j) or its salt carry out the triple bond reduction reaction, can prepare purpose compound (I h) or its salt.
Can carry out the reaction of present method according to the method that triple bond is reduced to two keys of routine, for example use shortenings such as Lindler catalyzer.
Method 9
By making compound (I f) or its reactive derivative or its salt on carboxyl carry out esterification, can prepare purpose compound (I k) or its salt.
The acceptable acid addition salts of compound (I k) can be considered to the acid salt that exemplifies for compound (I).
This esterification can be passed through compound (I f) or its reactive derivative or its salt and conventional esterifying reagent on carboxyl, for example low-carbon alcohol (as methyl alcohol, ethanol, propyl alcohol, butanols, the trimethyl carbinol, amylalcohol, hexanol etc.) is carried out according to the similar approach of method 5.
Method 10
By making compound (I l) or its salt carry out the lower alkanes glycosylation reaction, can prepare purpose compound (I m) or its salt.
The acceptable acid addition salts of compound (I l) and (I m) can be considered to the acid salt that exemplifies for compound (I).
The lower alkanes glycosylation reaction of present method can be by the low-carbon alkyl agent with compound (I l) or its salt and routine, low-carbon alkyl halogen (for example methyl iodide, methyl chloride, bromic ether, iodo propane, Iso-Propyl iodide, butyl iodide, tert-butyl chloride, bromo pentane, bromo hexane etc.) etc. for example, in conventional solvent (for example tetrahydrofuran (THF) etc.), react under the warm condition being cooled to.
Method 11
By making compound (I l) or its salt carry out acylation reaction, can prepare purpose compound (I n) or its salt.
The acceptable acid addition salts of compound (I n) can be considered to the acid salt that exemplifies for compound (I).
The acylation reaction of present method can be by making compound (I l) or its salt and conventional acylating agent; for example low carbon chain alkanoic acid (for example formic acid, acetate, propionic acid, butyric acid, isopropylformic acid, trimethylacetic acid, caproic acid etc.), its acyl halide, its acid anhydrides etc.; in conventional solvent (for example pyridine etc.), under the condition that is cooled to heat, react and carry out.
Method 12
By making compound (I o) or its salt carry out the elimination reaction of carboxyl-protecting group, can prepare purpose compound (I p) or its salt.
The acceptable acid addition salts of compound (I o) can be considered to the acid salt that exemplifies for compound (I).
The acceptable acid addition salts of compound (I p) is considered to the compound that exemplifies for compound (I).
The elimination reaction of present method can be according to carrying out with method 4 similar methods.
Method 13
By making compound (I q) or its salt carry out nitro-reduction reaction, can prepare purpose compound (I r) or its salt.
The acceptable acid addition salts of compound (I q) and (I r) can be considered to the compound that exemplifies for compound (I).
This reaction can be carried out according to the method with nitroreduction one-tenth amino of routine, for example by using metal or its salt (for example tin, tin protochloride, iron, iron protochloride, ferrous sulfate, zinc etc.) and acid (for example hydrochloric acid, sulfuric acid, acetate etc.) together.
Method 14
By making compound (I r) or its salt introduce the reaction of amino protecting group, can prepare purpose compound (I s) or its salt.
The acceptable acid addition salts of compound (I r) and (I s) can be considered to the compound that exemplifies for compound (I).
The reagent that this reaction can be passed through compound (I r) or its salt and conventional introducing amido protecting group carries out in being cooled to heat reaction down in conventional solvent (for example methylene dichloride, toluene, N, dinethylformamide etc.).The conventional reagent of introducing the amido protecting group is for example low carbon chain alkanoic acid, its acyl halide and above-mentioned its acid anhydrides; Halo formic acid low-carbon alkyl (for example methyl-chloroformate, Vinyl chloroformate, bromine propyl formate, isopropyl chlorocarbonate, bromine butyl formate, the chloroformic acid tert-butyl ester, amyl chlorocarbonate, the own ester of chloroformic acid etc.); Lower alkanes sulfonic acid halide (for example methane sulfonyl chloride, ethanesulfonyl chloride, propane SULPHURYL CHLORIDE, different propane SULPHURYL CHLORIDE, butane sulfuryl bromide, uncle's butane SULPHURYL CHLORIDE, pentane SULPHURYL CHLORIDE, hexane SULPHURYL CHLORIDE etc.); Above-mentioned low-carbon alkyl halogen, etc.
Method 15
By compound (VI) or its salt and compound (VII) or its salt are reacted, can prepare purpose compound (I d) or its salt.
The acceptable acid addition salts of compound (VII) can be considered to the compound that exemplifies for compound (I).
The acceptable acid addition salts of compound (VI) can be considered to the acid salt that exemplifies for compound (I).
This reaction preferably have acid in the presence of carry out for example Lewis acid (as aluminum halide (for example aluminum chloride etc.), halogenation boron (for example boron trifluoride etc.)), mineral acid (for example hydrochloric acid, sulfuric acid etc.), organic acid (for example acetate etc.) etc.
This reaction is normally at conventional solvent, for example methylene dichloride, chloroform, tetrahydrofuran (THF), N, and dinethylformamide, or carry out in any other solvent that reaction is had no adverse effect.
Temperature of reaction is inessential, and reaction can or be warming under the heating in cooling, room temperature to be carried out.
Method 16
By making compound (VIII) or its at the reactive derivative on the carboxyl or its salt and N-replaces amine (V) or its reactive derivative or its salt on amino reacts, can prepare purpose compound (I t) or its salt.
The acceptable acid addition salts of compound (I t) and (VIII) can be considered to exemplify for compound (I).
According to carrying out this reaction with method 5 similar modes.
Method 17
By making compound (I x) or its salt carry out the nitroso-group reduction reaction, can prepare purpose compound (I u) or its salt.
The acceptable acid addition salts of compound (I u) and (I x) can be considered to the acid salt that exemplifies for compound (I).
The reaction of present method can be carried out according to the amino method that nitroso-group is reduced to of routine, and this method is considered to the example of nitroreduction method in the method 13.
Under the organic acid situation that for example the low carbon chain alkanoic acid uses as acid, the amino of generation further reacts with above-mentioned acid sometimes, obtain corresponding protection amino, this situation also belongs in the scope of the invention.
Method 18
(I is v) introduced the reaction of amido protecting group, can prepare purpose compound (I w) or its salt by making compound.
Compound (I v) or the acceptable acid addition salts of (I w) can be considered to the acid salt that exemplifies for compound (I).
Carry out this reaction according to the mode that is similar to method 14.
Need to prove that because asymmetric carbon atoms and two key, purpose compound (I) can comprise one or more steric isomers, all these isomer and composition thereof all are included in the scope of the present invention.
What need further specify is because the effect of light, acid, alkali etc. may make purpose compound (I) that isomerization or rearrangement take place, this isomerization or reset after the compound that obtains be also included within the scope of the invention.
Purpose compound of the present invention (I) and salt thereof have hemangiectasis activity and increase kidney blood flow activity, therefore can be used as diuretic(s), hypotensive agent and treatment effectively and suffer from a deficiency of the kidney; This compound also has the platelet aggregation of inhibition activity, so also can be used for the treatment of thrombosis effectively; In addition, they also have cardiac activity, so can be used as cardiotonic drug effectively.
By purpose compound of the present invention (I) or its salt are applied to human body or animal body, can be used to treat oedema, hypertension, suffer from a deficiency of the kidney, thrombosis and congenital heart disease.
In order to show this purposes of The compounds of this invention (I), several pharmacology test results of the representative compound of the present invention are expressed as follows.
Test 1. hemangiectasis activities
(I) test method
The male SD kind mouse bloodletting of body weight 200～300g is killed, remove thorax artery, (2.0 * 15mm) are suspended in the organ bath that is full of 25ml Tai Luode test solution, and this is connected with strain gage, wait to hold and measure tension force, use 95%O with this spiral groove
2And 5%CO
2Mixed gas make the body lotion bubbling, and maintain 37 ℃, resting tension is transferred to 0.5g after, with 3.2 * 10
-8The norepinephrine of M shrinks the artery bar.
In organ bath, slowly add investigational agent, when each off-test, in organ bath, add 10
-4The M Papaverine is maximum lax to obtain.
(II) test compound
(2R)-1-(3-(the 2-phenylpyrazole is (1,5-a) pyridin-3-yl)-acryloyl also)-2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
(compound of embodiment 22)
(III) test-results
I c50 value=5.3 * 10
-7(g/ml)
Test 2. increases the activity of the blood flow of kidney
(I) test method
Use the adult police dog of body weight 8～15kg either gender, under with vetanarcol (35mg/kg ip) anesthesia, the conduit that artificial respiration is used inserts tracheae, for dispenser is put into femoral artery with conduit.
Cut flank, a bit of left renal artery is revealed put, remove adhering tissue, in position place an Electromagnetic Flow probe, the flow probe is connected to measures the kidney blood flow on the under meter.
(II) test compound
Identical compound in the use-testing 1.
(III) test-results
| Dosage (mg/kg) | Kidney blood flow increment rate (%) |
| 0.1 | +19.7 |
Test 3. diuretic activities
(I) test method
Use 6 weeks of age after hungry 18 hours, the male JcL of body weight 170～206g: SD kind mouse, behind the trial drug of oral suspension in 0.5% methylcellulose gum (0.5%MC), immediately with the oral normal saline solution of the amount of 20ml/kg, per three mouse are placed in the metabolic cage, collected urine 3 hours, and measured the urine volume with graduated cylinder; Use UA Kit
R(Kyowa Medex Co., Ltd.) survey meter is measured the uric acid in the urine, and test divides 3 groups and carries out every group of 3 animals.
(II) test compound
Identical compound in the use-testing 1.
(III) test-results
The drainage of urine and uric acid
(contrast=100%)
| Dosage (mg/kg) | The drainage (%) of urine | The drainage of uric acid (%) |
| 10 | 344 | 125 |
Test 4. antihypertensive actives
(I) test method
The male Wistar rats in 11 weeks of age is behind unilateral nephrectomy under the anesthesia, and subcutaneous injection is suspended in the Doca acetic ester (DOCA) in the peanut oil for twice weekly, and consumption 30mg/kg replaces tap water with 1% salt solution.
Mean blood pressure is 5 to 13 weeks to be used to do experiment behind the animal surgery of 150～200mmHg.
DOCA hypertension rat oral test every day compound (dosage: 10mg/kg), took 5 days.
Measure blood pressure by sensator at femoral artery, the electrodeposition score value of record average artery pressure.
(II) test compound
Identical compound in the use-testing 1.
(III) test-results
The maximum minimizing value (%)=27 of blood pressure
Test 5. platelet aggregations and suppress active
(I) test method
Collect blood from the male Japan rabbit carotid artery of body weight 2.5～3.0kg, mix with the sodium of 3.8% citric acid of 1/10 volume, this mixture is after 150 * g is centrifugal 15 minutes, obtain the blood plasma (PRP) of thrombocyte enrichment, measure hematoblastic cohesion with assembling instrument (Nikohkizai, NKK HEMA TRACER, PAT-4A type), will contain 6.5-7.5 * 10
8The 0.24ml PRP of thrombocyte/ml and testing liquid or the PEG200 of 5 μ l: ethanol: water (1: 1: 2) adds in the cuvette continuously, this mixture stirred 2 minutes down at 37 ℃, the 125 μ g/ml osso-albumins that add 5 μ l, to produce cohesion, use the PRP that from 3 different rabbits, obtains to test.
(II) test compound
Identical compound in the use-testing 1.
(III) test-results
It is active that platelet aggregation suppresses
IC
50Value=7.9 * 10
-6(g/ml)
Test 6. cardiac activities
(I) test method
The male Hartley kind cavy bloodletting of body weight 500～600g is killed, remove heart, shift out the artery bar and be suspended in and contain in the organ bath of Tai Luode test solution that 50ml remains on 30 ℃, feed 95%O
2-5%CO
2Mixed gas, under initial tension 0.4-0.6g, the atrium is connected on the strain gage, obtain constant fluctuation after, in body lotion, add medicine, observe the effect to convergent force and pollex speed in 30 minutes, its result with before taking medicine and the percentage value after taking medicine represent.Every kind of concentration is used 3 preparation liquid.
(II) test compound
Identical compound in the use-testing 1.
(III) test-results
| The concentration of test compound (g/ml) | The increase of convergent force (%) | The increase of heart rate (%) |
| 10 -6 | 10.0 | -10.7 |
Test 7. antihypertensive actives
(I) test method
The male Wistar rats in 11 weeks of age is behind unilateral nephrectomy under the anesthesia, and 2 subcutaneous injections are suspended in the Doca acetic ester (DOCA) in the peanut oil weekly, and dosage is 30mg/kg, and the salt solution with 1% replaces tap water.
Using mean blood pressure is testing in animal 5 to 13 weeks after operation of 150～200mmHg.
DOCA hypertension rat oral test every day compound (dosage: 3.2mg/kg) take five days.
Measure blood pressure by sensator at femoral artery, the electrodeposition score value of record average artery pressure.
(II) test compound
1-(3-(the 2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryloyl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide)) (compound of embodiment 9).
(III) test-results
| The maximum of blood pressure reduces (%) |
| 32 |
For treatment, purpose compound of the present invention (I) and pharmaceutically acceptable salt thereof can use by conventional pharmaceutical dosage forms, said preparation is take this compound as active component, mix with pharmaceutically acceptable carrier, for example organic or inorganic solid or liquid excipient, they are applicable to oral, injection and external application.
Pharmaceutical preparation can be solid form, such as tablet, granula, pulvis, capsule; Or liquid form, such as solution, suspension, syrup, emulsion, lemonade etc.
If need, can in above-mentioned preparation, add auxiliary substance, stabilizing agent, wetting agent and other general additive, such as lactose, citric acid, tartaric acid, stearic acid, dolomol, land plaster, sucrose, cereal starch, talcum, gelatin, agar, pectin, peanut oil, liver oil, cocoa butter, 1,2-ethylidene glycol etc.
Simultaneously, the dosage of compound (I) can change according to the factors such as kind of age, status of patient, kinds of Diseases, use compound (I). Usually, but to a patient medication 1mg to 1000mg every day even more, approximately the average UD of the object of the invention compound (I) of 1mg, 5mg, 10mg, 20mg can be used as diuretics, rescinnamine, treatment and suffers from a deficiency of the kidney, treats thrombotic medicine or cardiotonic.
The following preparation method who provides and embodiment are in order to explain in more detail the present invention. 34
Embodiment 1
With 2-Phenylpyrazole also (1,5-a) pyridine-3-formaldehyde (0.5g) and semicarbazides hydrochloride (0.25g) mixture in ethanol (7ml) refluxed 1 hour, then cooling, the sediment that generates filters, from the mixture of water and ethanol, be recrystallized, obtain also (1,5-a) pyridine-3-formaldehyde semicarbazones (0.26g) of 2-Phenylpyrazole.
mp：221-222℃
The IR(atoleine): 3350,1660,1570Cm-1
NMR（DMSO-d
6，δ）：6.33（2H，S）、7.00-7.90（7H，m）、8.27（1H，S）、8.43（1H，dd，J＝1.0、8.0Hz）、8.85（1H、d，J＝6.5Hz）、9.97（1H，s）
MS：279（M
+）。
Embodiment 2
With (2-(dimethylamino) acetyl) hydrazides dihydrochloride (624mg) and the heating under 60 ℃ of the mixture of potash (910mg) in ethanol (7ml), add 2-Phenylpyrazole also (1 in this mixture, 5-a) pyridine-3-formaldehyde (666mg), and refluxed 2.5 hours, after the cooling, this mixture filters, evaporated filtrate in the vacuum. Mixture with chloroform and methyl alcohol (2: 1) upward carries out chromatographic isolation to residue as eluant, eluent at silica gel (20g). Merge the cut that contains the purpose compound, and in a vacuum evaporation, residue is recrystallized from ethanol, obtains also (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) acetyl group of 2-Phenylpyrazole) hydrazone crystallization (0.63g).
mp：172-173℃
The IR(atoleine): 1670,1620Cm-1
NMR（CDCl
3，δ）：2.33（3H，S）、3.13（2H，S）、6.95（1H，dt，J＝2.0、7.0Hz）、7.30-7.83（7H，m）、8.37（1H，S）、8.53（1H，dd，J＝1.0、7.5Hz）、9.83-10.0（1H，m）。
MS：321（M
+）。
C
18H
19N
5The O elementary analysis:
Calculated value: C:67.27, H:5.96, N:21.79
Experiment value: C:67.65, H:5.96, N:21.80
Embodiment 3
Obtain also (1,5-a) pyridine-3-formaldehyde (2-(2-ethyl piperidine subbase) acetyl group of 2-Phenylpyrazole according to method similar to Example 2) hydrazone.
mp：156-157.5℃。
The IR(atoleine): 3200,1660,1625,1595,1520Cm-1。
NMR（CDCl
3, δ): 0.90(3H, t, J=7.0Hz) 1.13-2.00(8H, m), 2.20-2.67(2H, m), 2.77-3.10(1H, m), 3.07(1H, d, J=17.0Hz) 3.50(1H, d, J=17.0Hz), 7.02(1H, t, J=7.0Hz), 7.30-7.90(6H, m), 8.43-8.73(3H, m), 10.10(1H, wide, S).
MS：389（M
+）
C
23H
27N
5The O elementary analysis:
Calculated value: C:70.93, H:6.99, N:17.98
Experiment value: C:70.88, H:6.93, N:17.98
Embodiment 4
With 2-Phenylpyrazole also (1,5-a) pyridine-3-formaldehyde (0.5g) and hydroxy amine hydrochloric acid salt (0.17g) mixture in ethanol (5ml) refluxed 1.5 hours, and in a vacuum evaporation, grind residue with ethyl acetate, from ethanol and ethyl acetate mixture, be recrystallized, obtain also (1,5-a) pyridine-3-formaldoxime hydrochloride (0.28g) of 2-Phenylpyrazole.
mp：156-157℃
The IR(atoleine): 2380,1620Cm-1
NMR（DMSO-d
6，δ）：7.07-8.17（9H，m）、8.80（1H，d，J＝8Hz）、10.33（1H，S）
MS：237（M
+）
Embodiment 5
To 2-Phenylpyrazole also (1,5-a) in the pyridine-mixture of 3-formaldoxime (0.52g) in chloroform (4ml), under stirring and ice-cooled condition, carrene (2ml) the liquid liquid that dropwise adds methyl isocyanate (0.19g), this mixture at room temperature stirred 2 hours, and at room temperature leave standstill a night, evaporating solvent in a vacuum, upward residue carried out chromatographic isolation as eluant, eluent at silica gel (20g) with carrene, merge the cut (20ml) and the in a vacuum evaporation that contain the purpose compound, residue is recrystallized from ethyl acetate, obtains also (1,5-a) pyridine-3-nitrile (0.21g) of 2-Phenylpyrazole.
mp：138-139℃
The IR(atoleine): 2220,1620Cm-1
NMR（CDCl
3，δ）：7.03（1H，dt，J＝2.0、7.0Hz）、7.43-7.93（5H，m）、8.03-8.37（2H，m）、8.58（1H，dd，J＝1.0、7.0Hz）
MS：219（M
+）。
Embodiment 6
With 2-Phenylpyrazole also (1,5-a)-pyridine-3-formaldehyde (0.50g) and acetonylidene triphenyl phosphorane
(0.82g) mixture in benzene (6ml) refluxed 4 hours, then solvent evaporated in a vacuum. Upward residue carried out chromatographic isolation as eluant, eluent at silica gel (20g) with chloroform, merge the cut and the in a vacuum evaporation that contain the purpose compound, residue is recrystallized from ethanol, obtain also (1,5-a) pyridin-3-yl-3-fourth-2-ketone (transisomer) crystal (0.21g) of 4-(2-Phenylpyrazole.
mp：134.5～135.5℃
The IR(atoleine): 1650,1600,1500Cm-1
NMR（CDCl
3，δ）：2.37（3H，S）、6.67（1H，d，J＝16.0Hz）、7.00（1H，dt，J＝2.0、6.0Hz）、7.10-8.07（9H，m）、8.63（1H，d，J＝6.0Hz）。
MS：262（M
+）
C
17H
14N
2The O elementary analysis:
Calculated value: C:77.84, H:5.38, N:10.68
Experiment value: C:78.55, H:5.40, N:10.65.
Embodiment 7
In the mixture of sodium hydride (63%, 880mg) in toluene (45ml); under stirring and cooling condition; toluene (10ml) solution that adds trimethyl-phosphine acyl acetic acid (4.0g); then 60 ℃ of lower heating 20 minutes; add 2-Phenylpyrazole also (1 in this mixture; 5-a) pyridine-3-formaldehyde (2.0g); 60 ℃ of lower heating 8 hours; in reactant mixture, add saturated solution of sodium bicarbonate (30ml); with ethyl acetate (30ml; 2 times) extraction, with salt solution (30ml) washing extract, use dried over mgso; and in a vacuum evaporation; residue is recrystallized from ethyl acetate and isopropanol mixture, has obtained also (1,5-a) pyridin-3-yl of 3-(2-Phenylpyrazole) methyl acrylate (transisomer) crystal (1.34g).
mp：139-139.5℃
The IR(atoleine): 1700,1610Cm-1
NMR（CDCl
3，δ）：3.77（3H，S）、6.28（1H，d，J＝16Hz）、6.88（1H，dt，J＝1.5、6.0Hz）、7.20-7.90（7H，m）、7.92（1H，d，J＝16Hz）、8.50（1H，d，J＝6.0Hz）。
MS：278（M
+）
Embodiment 8
With 3-(2-phenylpyrazole (1.5-a) pyridin-3-yl also) methyl acrylate (trans-isomer(ide)) (4.05g) mixture in 1N sodium hydroxide solution (58.3ml) and methyl alcohol (80ml) refluxed 1 hour, and evaporation in a vacuum, residuum is soluble in water, wash with chloroform, with 1N hcl acidifying water layer, the precipitation that generates is filtered, and recrystallization from Virahol obtains also (1.5-a) pyridin-3-yl of 3-(2-phenylpyrazole) vinylformic acid crystal (2.65g).
mp：225-225.5℃
The IR:(whiteruss): 1660,1590cm
-1
NMR：（DMSO-d
6、δ）：6.32（1H.d.J＝16.0Hz），7.15（1H.dt.J＝1.0、6.0Hz）、7.40-7.92（7H，m）、8.10（1H，d.J＝7.0Hz）、8.87（1H，d.J＝6.0Hz）
MS：264（M
+）
C
16H
12N
2O
2Ultimate analysis
Calculated value: C:72.72, H:4.58, N:10.60
Experimental value: C:73.13, H:4.50, N:10.67
Embodiment 9
Also (1.5-a) pyridin-3-yl vinylformic acid (trans-isomer(ide)) is (2.0g) and the mixture of triethylamine (0.766g) in methylene dichloride (40ml) and tetrahydrofuran (THF) (10ml) to the 3-(2-phenylpyrazole, at-20 ℃, dropwise add isobutyl chlorocarbonate down in stirring, after same temperature stirs 30 minutes, at-20 ℃, tetrahydrofuran (THF) (10ml) solution that adds 2-ethyl piperidine (0.942g) gradually, stirred this mixture 2 hours down at-20 ℃-10 ℃, with this mixture heating up to room temperature, and evaporation in a vacuum, in residuum, add saturated solution of sodium bicarbonate, with chloroform (50ml) extracting twice, extraction liquid with saturated brine (50ml) washing merging, use dried over mgso, and evaporation in a vacuum, upward residuum carried out chromatographic separation as eluent at silica gel (40g) with chloroform, merge the cut that contains the purpose compound, evaporation obtains 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryloyl in a vacuum)-2-ethyl piperidine (trans-isomer(ide)) oily matter (1.30g).
This compound is transformed into 1/2 fumarate by general method, this crystal is recrystallization from the mixture of normal hexane and diethyl ether, obtains 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryloyl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide)) yellow crystals (0.96g).
mp：121-122℃
The IR(whiteruss): 1705,1635,1580,1540,1510cm
-1
NMR（DMSO-d
6，δ）：0.77（3H，t，J＝7.0Hz）、1.30-1.83（8H，m）、6.66（1H，S）、6.83（1H，d，J＝16.0Hz）、7.00-7.83（8H，m）、8.07（1H，d，J＝9.0Hz）、8.77（1H，d，J＝7.0Hz）
C
23H
25N
3O1/2C
4H
4O
4Ultimate analysis:
Calculated value: C:71.92, H:6.52, N:10.06
Experimental value: C:72.01, H:6.60, N:10.03
Obtain following compounds (embodiment 10-17) according to method similar to Example 9
Embodiment 10
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryloyl)-tetramethyleneimine (trans-isomer(ide))
mp：190-191℃
The IR(whiteruss): 1640,1590cm
-1
NMR（CDcl
3，δ）：1.70-2.30（4H，m）、3.33-3.90（4H，m）、6.53（1H，d，J＝16.0Hz）、6.77-8.13（8H，m）、
8.57（1H，d，J＝7.0Hz）
C
20H
19N
3The O ultimate analysis:
Calculated value: C:75.69, H:6.03, N:13.24
Experimental value: C:76.08, H:5.95, N:13.16
MS：317（M
+）
Embodiment 11
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryloyl)-piperidines (trans-isomer(ide))
mp：111.5～112℃
The IR(whiteruss): 1630,1580cm
-1
NMR(CDcl
3, δ): 1.40-1.75(6H, m), 3.30-3.70(4H wide, S), 6.65(1H, d, J=15.0Hz), 6.83(1H, dt, J=2.0,6.0Hz), 7.13-7.80(7H, m), 7.83(1H, d, J=15.0Hz), 8.45(1H, d, J=6.0Hz)
C
21H
21N
3The O ultimate analysis:
Calculated value: C:76.11, H:6.39, N:12.68
Experimental value: C:76.08, H:6.32, N:12.65
MS：331（M
+）
Embodiment 12
4-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryloyl)-morpholine (trans-isomer(ide))
mp：154.5-155.5℃
The IR(whiteruss): 1625,1580cm
-1
NMR(CDcl
3, δ): 3.63(8H, wide S), 6.60(1H, d, J=16.0Hz), and 6.90(1H, dt, J=2.0,7.0Hz), 7.15-7.83(7H, m), and 8.00(1H, d, J=16.0Hz), and 8.50(1H, dd, J=1.0,7.0Hz)
MS：333（M
+）
C
20H
19N
3O
2Ultimate analysis:
Calculated value: C:72.05, H:5.74, N:12.60
Experimental value: C:72.55, H:5.72, N:12.58
Embodiment 13
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryloyl)-4-methylpiperazine hydrochloride (trans-isomer(ide))
mp：261-262℃
The IR(whiteruss): 2400,1650,1580,1500cm
-1
NMR（DMSO-d
6，δ）：2.78（3H，S），3.00-3.70（8H，m），6.99（1H，d，J＝11Hz）7.00-7.83（7H，m），7.76（1H，d，J＝11Hz），8.21（1H，d，J＝6.0Hz），8.90（1H，d，J＝5.0Hz）
C
21H
22N
4The OHcl ultimate analysis
Calculated value: C:65.88, H:6.05, N:14.63
Experimental value: C:65.90, H:6.01, N:14.66
Embodiment 14
N-methyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acrylamide (trans-isomer(ide))
mp：208-209℃
The IR(whiteruss): 3275,1640,1605cm
-1
NMR（DMSO-d
6，δ）：2.73（3H，d，J＝5.0Hz）、6.77（1H，d，J＝16.0Hz），7.0-8.10（9H，m），8.90（1H，d，J＝6.0Hz）
MS：277（M
+）
Embodiment 15
N-sec.-propyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
mp：210-210.5℃
The IR(whiteruss): 3275,1640,1600cm
-1
NMR（CDcl
3，δ）：1.22（3H，d，J＝7.0Hz）6.23（1H，d，J＝16.0Hz），6.90（1H，dt，J＝2.0，7.0Hz），7.20-8.07（8H，m），8.53（1H，dd，J＝2.0，7.0Hz）
C
19H
19N
3The O ultimate analysis:
Calculated value: C:74.73, H:6.27, N:13.76
Experimental value: C:74.96, H:6.16, N:13.80
MS：305（M
+）
Embodiment 16
N, N-dimethyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
mp：154-155℃
The IR(whiteruss): 1640,1590cm
-1
NMR（CDcl
3，δ）：3.05（6H，S），6.70（1H，d，J＝16.0Hz），6.87（1H，dt，J＝2.0，7.0Hz），7.15-7.78（7H，m），7.95（1H，d，J＝16.0Hz），8.50（1H，dd，J＝1.0，7.0Hz）
C
18H
17N
3The O ultimate analysis:
Calculated value: C:74.21, H:5.88, N:14.42
Experimental value: C:74.44, H:5.86, N:14.42
MS：291（M
+）
Embodiment 17
N-(three rings (3,3,1,1
3.7) last of the ten Heavenly stems-the 1-yl)-3-(2-phenylpyrazole (1,5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
mp：232.5-233.5℃
The IR(whiteruss): 3280,1650,1590,1535,1500cm
-1
NMR(CDcl
3, δ): 1.53-1.83(6H, m), 1.90-2.27(9H, m), 5.23(1H, wide S), 6.22(1H, d, J=16.0Hz), 6.90(1H dt, J=1.0,7.0Hz), 7.30(1H, t, J=6.0Hz), 7.43-7.97(7H, m), 8.57(1H, d, J=6.0Hz)
C
26H
27N
3The O ultimate analysis
Calculated value: C:78.56, H:6.85, N:10.57
Experimental value: C:77.85, H:7.01, N:10.30
MS：397（M
+）
Embodiment 18
To 3-(2-phenylpyrazole also (1,5-a) pyridin-3-yl) vinylformic acid (trans-isomer(ide)) (4.0g) triethylamine (1.53g) at N, in the mixture in the dinethylformamide (40ml), under-20 ℃ of stirrings, dropwise add isobutyl chlorocarbonate (2.07g), under uniform temp, stir after 30 minutes, the N that under-20 ℃, dropwise adds (2R)-2-ethyl piperidine (1.88g), dinethylformamide (20ml) solution, mixture stirred 2 hours down at-20 ℃～-10 ℃.
In reaction mixture impouring water (100ml), with ethyl acetate (50ml) extracting twice,, use the sulphur dried over mgso with the extraction liquid that saturated aqueous sodium chloride (30ml) washing merges, and evaporation in a vacuum.
Upward residuum carried out chromatographic separation as eluent at silica gel (80g) with chloroform, merge the cut that contains the purpose compound, and evaporation in a vacuum, obtain (2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryloyl)-2-ethyl piperidine (trans-isomer(ide)) oily matter (3.13g).
(α)
26 D=-34.30 ° (C=1.0, ethanol)
The IR(film): 2930,2860,1635,1585cm
-1
NMR(CDcl
3, δ): 0.85(3H, t, J=7.0Hz), 1.43-1.90(6H, m), 2.50-3.20(1H, m), 3.83-4.73(2H, m), 6.70(1H, d, J=16.0Hz), 6.88(1H, dt, J=1.5Hz and 7.0Hz), 7.17-7.93(7H, m), 7.97(1H, d, J=16.0Hz), 8.54(1H, dd, J=1.0Hz and 7.0Hz)
MS：359（M
+）
Embodiment 19
By usual method with (2R)-1-(3-(2-phenylpyrazole also (1,5-a) pyridin-3-yl)-acryloyl)-2-ethyl piperidine (trans-isomer(ide)) (1.79g) changes into hydrobromate, with crystal recrystallization from the mixture of ethyl acetate and acetone, obtain (2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryloyl)-2-ethyl piperidine hydrobromate (reaction isomer) yellow crystals (1.48g).
mp：103-104℃
The IR(whiteruss): 1630,1600,1500cm
-1
NMR(DMSO-d
6, δ): 0.78(3H, t, J=7Hz), 1.18-1.87(6H, m), 2.70-3.23(1H, m), 4.00-3.67(2H, m), 6.91(1H, d, J=15.0Hz), 7.12(1H, dt, J=2.0Hz and 7.0Hz), 7.33-8.26(10H, m), 8.42(1H, S), 8.83(1H, d, J=7.0Hz)
(α)
26.4 D=-29.39 ° (C=0.966, ethanol)
Embodiment 20
To 3-(2-phenylpyrazole also (1,5-a) pyridin-3-yl)-vinylformic acid (trans-isomer(ide)) (4.0g) and triethylamine (1.53g) at N, mixture in the dinethylformamide (40ml), at-20 ℃, dropwise add isobutyl chlorocarbonate (2.07g) down in stirring, after stirring 30 minutes under the same temperature, under-20 ℃, the N that dropwise adds (2S)-2-ethyl piperidine (1.88g), dinethylformamide (20ml) solution, this mixture stirred 2 hours down at-20 ℃～-10 ℃.
In reaction mixture impouring water (100ml), with ethyl acetate (50ml) extracting twice,, use dried over mgso with the extraction liquid that saturated aqueous sodium chloride (30ml) washing merges, dry under vacuum.
Upward residuum is carried out chromatographic separation with the chloroform give eluent at silica gel (80g); merge the cut that contains the purpose compound; and evaporation in a vacuum; obtain (2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide)) oily matter.
(α)
26 D=+34.80 ° of (C=1.0; Ethanol)
The IR(film): 2930,2860,1635,1585cm
-1
NMR（CDcl
3，δ）：0.85（3H，t，J＝7.0Hz）
1.43-1.90(6H, m), 2.50-3.20(1H, m), 3.83-4.73(2H, m), 6.70(1H, d, J=16.0Hz), 6.88(1H, dt, J=1.5Hz and 7.0Hz), 7.17-7.93(7H, m), 7.97(1H, d, J=16.0Hz), 8.54(1H, dd, J=1.0Hz and 7.0Hz)
MS：359（M
+）
Embodiment 21
With (2S)-1-(3-(2-phenylpyrazole also (1; 5-a) acryl pyridin-3-yl))-2-ethyl piperidine (trans-isomer(ide)) (2.11g) changes into hydrobromate by general method; this crystal is recrystallization from the mixture of ethyl acetate and acetone, obtains (2S)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine hydrobromate (trans-isomer(ide)) yellow crystals (1.75g).
mp：104-105℃
The IR(whiteruss): 1630,1600,1500cm
-1
NMR（DMSO-d
6，δ）：0.78（3H，t，
J=7.0Hz), 1.18-1.87(6H, m), 2.70-3.23(1H, m), 4.00-3.67(2H, m), 6.88(1H, d, J=16.0Hz), 7.11(1H, dt, J=2.0Hz and 7.0Hz), 7.36-8.28(10H, m), 8.77(1H, S), and 8.83(1H, d, J=7.0Hz)
(α)
26.4 D=+29.91 ° of (C=0.926; Ethanol)
Embodiment 22
To the 3-(2-phenylpyrazole that is stirring (1.5-a) pyridin-3-yl also) vinylformic acid (trans-isomer(ide)) is (2.00g) and N, in the mixture of dinethylformamide (4) in methylene dichloride (10ml), in the ice-cooled thionyl chloride (1.79g) that dropwise adds down.
After at room temperature stirring 3 hours, steam solvent in a vacuum, obtain chloride derivative.
On the other hand, under ice-cooled, in two-(trimethyl silyl) ethanamide (6.80g), dropwise add (R)-2-(2-hydroxyethyl) piperidines (6.48g), the mixture stirring was heated to room temperature in 20 minutes.
In mixture, add triethylamine (1.53g) and methylene dichloride (40ml), at the ice-cooled above-mentioned chloride derivative of adding in this mixture down, at room temperature stirred 1 hour, solvent evaporated in the vacuum is then to the mixture that wherein adds 1N hydrochloric acid soln (10ml) and ethyl acetate (10ml).
After the mixture that obtains stirred 30 minutes; the sodium hydroxide solution (12ml) that in mixture, adds 1N; extract with methylene dichloride (60ml); the extraction liquid dried over mgso; and steam solvent in a vacuum; mixture with methylene dichloride and ethyl acetate (5: 1) upward carries out chromatographic separation to residuum as eluent at silica gel (40g); merge the cut that contains the purpose compound; evaporation in a vacuum; obtain (2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide)) is (1.83g).
mp：145-146.5℃
(α)
24.0 D=+39.61 ° (C=1.04,95% ethanol)
The IR(whiteruss): 3350,1640,1575,1520ml
-1
NMR（CDcl
3，δ）：1.23-2.20（8H，m），2.63-3.90（4H，M），4.00-4.40（1H，m），4.67-5.10（1H，m），6.63（1H，d，J＝16.0Hz），8.50（1H，t，J＝7.0Hz），7.77（7H，m），7.92（1H，d，J＝16.0Hz），8.47（1H，d，J＝7.0Hz）
C
23H
25N
3O
2Ultimate analysis:
Calculated value: C:73.58, H:6.71, N:11.19
Experimental value: C:73.98, H:6.76, N:11.24
MS：375（M
+）
According to obtaining following compounds (embodiment 23 and 24) with embodiment 22 similar methods.
Embodiment 23
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide)).
Fusing point: 98～99.5 ℃
(α)
28.0 D=-41.20 ° (C=1.0,95% ethanol)
3330,1635,1570,1520Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.17～2.20(8H, m), 2.67～4.00(4H, m), 2.78(1H, s), 4.67～5.10(1H, m), 6.70(1H, d, J=16.0HZ), 6.89(1H, t, J=7.0Hz), 7.25～7.87(7H, m), 8.00(1H, d, J=16.0Hz), 8.57(1H, d, J=7.0Hz)
C
23H
25N
3O
2The computational analysis value:
C73.58，H6.71，N11.19
Experimental value: C73.68, H6.81, N11.21
Mass spectrum: 375(M
+).
Embodiment 24
(2RS)-1-3-(the 2-phenylpyrazole is (1,5-a) pyridin-3-yl) acryl also }-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide)).
Fusing point: 140.5～141.5 ℃
3280,1625,1560,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.17～2.20(8H, m) 2.54～3.90(5H, m), 4.67～5.10(1H, m), 6.64(1H, d, J=16.5Hz), 6.85(1H, dt, J=7.0Hz and 1.0Hz), 7.15～7.77(7H, m), 7.92(1H, d, J=16.5Hz), 8.47(1H, d, J=7,0Hz).
C
23H
25N
3O
2The computational analysis value:
C73.58、H6.71、N11.19
Experimental value: C73.50, H6.56, N11.14
Mass spectrum: 375(M
+).
The preparation method 1
At ambient temperature with 2-phenylpyrazole also (1,5-a) pyridine (2.00 gram) joins in acetic anhydride (4.20 gram) and the two vitriolic stirred solutions, under reflux state, stir after 14 hours, reaction mixture is poured on 80 milliliters of 4N aqueous sodium hydroxide solutions, and extracts with chloroform (30 milliliters * 2).Merge extract, water (30 milliliters), saturated sodium-chloride water solution (30 milliliters) washing back drying on sal epsom, and evaporation in a vacuum.Residual crystallisate gets also-(1,5-a) pyridine (1.16 gram) of 2-phenyl-3-acetyl pyrazole behind the recrystallization in diisopropyl ether.
Fusing point: 84～85 ℃
1640,1620,1495Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 2.23(3H, S) 7.04(1H, td, J=7Hz and 1Hz), 7.40～7.70(6H, m), and 8.51(2H, t, 7Hz).
C
15H
12N
2The computational analysis value of O:
C76.25、H5.12、N11.86
Experimental value: C77.25, H5.21, N11.87
Mass spectrum: 236(M
+)
The preparation method 2
The solution of SODIUMNITRATE (533 milligrams) in water (2.5 milliliters) is dropwise joined 2-phenyl-pyrazole also (1 under 13～15 ℃, 5-a) in the solution of pyridine (1.0 gram) in acetate (5 milliliters), under uniform temp, stir after 20 minutes, reaction mixture is poured on the frozen water.Collect the throw out that generates with filtering, wash back recrystallization in acetone with water and get the also xln of (1,5-a) pyridine (0.82 gram) of 3-nitroso-group-2-phenylpyrazole.
Fusing point: 161～163 ℃
Infrared spectra (whiteruss): 1620Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 7.28(1H, td, J=6.5Hz and 2.0Hz), 7.17-8.02(5H, m), 8.27-8.77(3H, m).
C
13H
9N
3The computational analysis value of O:
C69.94，H4.06，N18.83
Experimental value: C70.26 H4.18 N18.97
Mass spectrum: 223(M
+).
Embodiment 25
Ammonium chloride (298 milligrams) is joined 2-phenylpyrazole also (1 in batches under 5～6 ℃, 5-a) after at room temperature stirring is spent the night in pyridine (145 milligrams) and the solution of 3-dimethylamino ethyl propenoate (316 milliliters) in methylene dichloride (2 milliliters), reaction mixture is poured on the water (50 milliliters), neutralize with saturated sodium bicarbonate aqueous solution, and extract with chloroform (50 milliliters * 2).Extract, evaporates after drying on the sal epsom in a vacuum with saturated sodium-chloride water solution (20 milliliters) washing.Resistates separates with chromatography on silica gel, makes eluant with the mixture of chloroform and normal hexane (1: 1).Merge the cut that contains the purpose compound, evaporation obtains also (1,5-a) pyridin-3-yl of 3-(2-phenylpyrazole in a vacuum) ethyl propenoate (trans-isomer(ide)) (189.4 milligrams).
1690,1615,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.30(3H, t, J=6.0Hz), and 4.27(2H, q, J=6.0Hz), and 6.30(1H, d, J=16.0Hz), and 6.88(1H, td, J=6.0Hz and 2.0Hz), 7.16～8.33(8H, m), 8.53(1H, dd, J=8.0=Hz and 1.0Hz).
Embodiment 26
With 3-nitroso-group-2-phenylpyrazole also (1,5-a) pyridine (0.81 gram) and the mixture of zinc powder (0.95 gram) in acetate (10 milliliters) under refluxad heated 2.5 hours, reaction mixture is poured on the frozen water (100 milliliters), neutralizes with saturated sodium bicarbonate aqueous solution.Collect the throw out that generates by filtering, wash back recrystallization in ethyl acetate with water, obtain also (1,5-a) pyridine xln (304 milligrams) of 3-acetylaminohydroxyphenylarsonic acid 2-phenylpyrazole.
Fusing point: 188～189 ℃
Infrared spectra (whiteruss): 3170,1640 1530Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 2.20(3H, S), and 6.87(1H, td, J=6.5Hz and 1.0Hz), 7.07～8.10(8H, m), 8.27～8.57(1H, m).
C
15H
13N
3The computational analysis value of O:
C71.69，H5.21，N16.72
Experimental value: C71.68, H4.75, N16.75
Mass spectrum: 251(M
+)
Embodiment 27
With 3-nitroso-group-2-phenylpyrazole also (1,5-a) pyridine (1.00 gram) zinc powder and the mixture of concentrated hydrochloric acid (0.4 milliliter) in ethanol (10 milliliters) reflux conditions heating 3 hours.
Ethanol evaporation under vacuum condition, mixture extracts with chloroform (30 milliliters * 2) with saturated sodium bicarbonate aqueous solution (20 milliliters) neutralization back.The extraction liquid that obtains is washed dry and evaporation in a vacuum on sal epsom with saturated nacl aqueous solution (20 milliliters).Coarse crystallization recrystallization in ethyl acetate obtains also (1,5-a) pyridine (531 milligrams) of 3-amino-2-phenylpyrazole.
Fusing point: 155-157 ℃
3360,3250,1625Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 3.13(2H, δ), and 6.60(1H, td, J=7.0Hz and 2.0Hz), 6.97(1H, td, J=7.0Hz and 1.0Hz), 7.27～8.10(2H, m), 7.83～8.10(2H, m), 8.32(1H, dd, J=7.0Hz and 1.0Hz).
C
13H
11N
3The computational analysis value:
C74.62，H5.30，N20.08
Experimental value: C74.88, H4.85, N20.15
Embodiment 28
2-ethoxy carbonyl Acetyl Chloride 98Min. (0.445 gram) is dropwise joined triethylamine (0.298 gram) and 3-amino-2-phenylpyrazole also in the solution of (1,5-a) pyridine (0.560 restrains) in methylene dichloride (10 milliliters) under ice-cooled condition.
After mixture is at room temperature placed and spent the night, mixture is poured in the saturated sodium-chloride water solution (20 milliliters), and extracted with chloroform (20 milliliters * 2).After the extraction liquid that obtains washs with saturated sodium-chloride water solution (20 milliliters), dry on sal epsom, and evaporation in a vacuum.Resistates is gone up with chromatography and is separated at silica gel (20 gram), uses the chloroform give eluant.Merge the cut contain the purpose compound, after the evaporation, recrystallization obtains 3-(2-ethoxy carbonyl kharophen in ethyl acetate in a vacuum)-the 2-phenylpyrazole xln of (1,5-a) pyridine (0.48 gram) also.
Fusing point: 160～161 ℃
3250,1740,1650,1570Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.32(3H, t, J=7.0Hz), 3.55(2H, S), 4.30(2H, q, J=7.0Hz), 6.79(1H, td, J=7.0Hz and 1.5Hz), 7.20(1H, t, J=7.0Hz), 7.38-7.67(4H, m), 7.70-8.10(2H, m), 8.45(1H, d, J=7.0Hz), 8.75(1H, wide S).
C
18H
17N
3O
3The computational analysis value:
C66.86，H5.30，N13.00
Experimental value: C67.21, H4.83, N13.10
Embodiment 29
Similar approach according to embodiment 1 obtains 3-(1-semicarbazono ethyl)-2-phenylpyrazole (1,5-a)-pyridine also.
Fusing point: 185～194 ℃
3750,3200,1685,1580Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 1.95(1.5H, S), 2.10(1.5H, S), 6.10～6.33(2H, m), 6.80～7.15(1H, m), 7.29～8.00(6H, m), 9.28(1H, S), 8.55～8.90(1H, m).
Mass spectrum: 293(M
+).
Following compound (embodiment 30 to 38) obtains according to the similar approach of embodiment 2.
Embodiment 30
4-methyl-2-phenylpyrazole is (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl also) hydrazone (mixture of E and Z).
Fusing point: 164～165 ℃
Infrared spectra (whiteruss): 3150,1660Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 2.17 and the total 6H of 2.25(, S),
2.67 and the total 3H of 2.71(, S), 3.02 and the total 2H of 3.07(, S), 6.88～7.98(7H, m), 8.46～8.86(2H, m).
C
19H
20N
5The computational analysis value of O:
C68.04，H6.31，N20.88
Experimental value: C68.33, H6.17, N21.07
Embodiment 31
5-methyl-2-phenylpyrazole is (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl also) hydrazone (mixture of E and Z).
Fusing point: 196～197 ℃
1675,1640,1600,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 2.27 and the total 6H of 2.38(, S), 2.49(3H, wide S), 3.00 and the total 3H of 3.52(, S), and 7.02(1H, wide d, J=7.0Hz), 7.48～8.38(6H, m), 8.64～8.90(2H, m).
C
19H
21N
5The computational analysis value of O:
C68.24，H6.03，N20.94
Experimental value: C67.96, H6.21, N20.68
Embodiment 32
7-methyl-2-phenylpyrazole is (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl also) hydrazone (individual isomer).
Fusing point: 151～153 ℃
3300,1660,1620,1590Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 2.33(6H, S), 2.82(3H, S), 3.12(2H, S), and 6.82(1H, d, J=6.5Hz), 7.23-7.83(6H, m), 8.37(1H, S), and 8.48(1H, d, J=6.5Hz), 9.93(1H, S).
C
19H
21N
5The computational analysis value of O:
C68.04，H6.31，N20.88
Experimental value: C68.29, H6.20, N20.29
Embodiment 33
The 2-(4-chlorophenyl) hydrazone (mixture of E and Z) pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl).
Fusing point: 202～205 ℃
3450,1660,1620Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 2.30 and the total 6H of 2.36(, S), 3.05 and the total 2H of 3.52(, S), and 7.17(1H, t, J=7.0Hz), 7.40～8.00(5H, m), 8.00～9.00(3H, m).
C
18H
18ClN
5The computational analysis value of O:
C60.76，H5.10，N19.68
Experimental value: C61.06, H5.08, N19.79
Mass spectrum: 354(M
+)
Embodiment 34
The 2-(2-chlorophenyl) hydrazone (individual isomer) pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl).
Fusing point: 167～168 ℃
3350,1660,1625,1600Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 2.30(6H, S), 3.10(3H, S), and 6.99(1H, t, J=7.0Hz), 7.30～7.77(6H, m), 7.99(1H, S), and 8.53(2H, d, J=7.0Hz).
C
18H
18ClN
5The computational analysis value of O:
C60.76，H5.10，N19.68
Experimental value: C60.95, H5.04, N19.56
Mass spectrum: 355(M
+)
Embodiment 35
The 2-(4-p-methoxy-phenyl) hydrazone hydrochloride (mixture of E and Z) pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl)
Fusing point: 233-236 ℃
1675,1630,1600Cm infrared spectra (whiteruss):
-1Nucleus magnetic resonance (DMSO-d
6, δ): 2.90 and the total 6H of 2.96(, S), 3.85(3H, S), 4.07 and the total 2H of 4.58(, S), 7.00～7.33(3H, m), 7.40～7.83(3H, m), 8.17～9.00(3H, m)
C
19H
21N
5O
2The computational analysis value of HCl:
C58.84，H5.72，N18.06
Experimental value: C59.20, H5.56, N17.91
Embodiment 36
The 2-(3-p-methoxy-phenyl) hydrazone (mixture of E and Z) pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethyl oxygen base) ethanoyl)
Fusing point: 145～147 ℃
1660,1625,1605,1575Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 2.25 and the total 6H of 2.35(, S), 3.01 and the total 2H of 3.53(, S), 3.87(3H, S), 7.05～7.67(6H, m), 8.20～8.93(3H, m)
C
19H
21N
5O
2The computational analysis value:
C64.95，H6.02，N19.93
Experimental value: C65.32, H5.86, N19.56
Mass spectrum: 351(M
+)
Embodiment 37
The 2-(3-nitrophenyl) hydrazone (mixture of E and Z) pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl)
Fusing point: 202～206 ℃
Infrared spectra (whiteruss): 1660,1625Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 2.30 and the total 6H of 2.35(, S) 3.05 and the total 2H of 3.47(, S), and 7.20(1H, t, J=7.5Hz), and 7.60(1H, t, J=7.5Hz), and 7.88(1H, t, J=7.5Hz), 8.15-8.74(5H, m), and 8.94(1H, d, J=7.5Hz)
C
18H
18N
6O
3The computational analysis value:
C59.01，H4.95，N22.94
Experimental value: C58.91, H4.74, N22.95
Embodiment 38
2-sec.-propyl pyrazolo (1,5-a) pyridine-3-formaldehyde (2-(dimethylamino) ethanoyl) hydrazone (individual isomer)
Fusing point: 140～141 ℃
1660,1630,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.42(6H, d, J=6Hz), 2.37(6H, S), 3.13(2H, S), 3.37(1H, septet, J=6.0Hz), 6.85(1H, td, J=6.5Hz and 2.0Hz), 7.33(1H, td, J=6.5Hz and 2.0Hz), 8.37(1H, d, J=6.5Hz), 8.43(1H, d, J=6.5Hz), 8.15(1H, S), 10.00(1H, wide S)
C
15H
21N
5The computational analysis value of O:
C62.70，H7.37，N24.37
Experimental value: C62.71, H7.16, N24.13
Following compound (embodiment 39 to 55) obtains according to the method that is similar to embodiment 22.
Embodiment 39
N, N-diethyl-3-(2-phenylpyrazole be (1,5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
1640,1595,1520Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.15(6H, t, J=7Hz), 3.10～3.78(4H, m), and 6.56(1H, d, J=16Hz), and 6.86(1H, td, J=7Hz and 1Hz), 7.22～7.90(7H, m), and 8.02(1H, d, J=16Hz), and 8.57(1H, d, J=7Hz)
C
20H
21N
3O1/2H
2The computational analysis value of O:
C73.14，H7.05，N12.79
Experimental value: C73.68, H6.52, N12.75
Mass spectrum: 319(M
+)
Embodiment 40
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-pipecoline (trans-isomer(ide))
1640,1590,1515Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.27(3H, d, J=6Hz), 1.42-1.97(6H, wide), 2.80～3.25(1H, m)
4.00-4.85(2H, m), 6.66(1H, d, J=16Hz), and 6.87(1H, td, J=7Hz and 1Hz) 7.21～7.83(7H, m), and 7.93(1H, d, J=16Hz), and 8.52(1H, d, J=7Hz)
C
22H
23N
3The computational analysis value of O:
C76.49，H6.71，N12.16
Experimental value: C75.48, H6.80, N12.06
Mass spectrum: 345(M
+)
Embodiment 41
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-propyl group piperidines (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.88～1.97(13H, m), 1.66～3.24(1H, wide), 3.70～5.20(2H, wide), 6.72(1H, d, J=16Hz6.92(1H, td, J=7Hz and 1Hz), 7.23～7.88(7H, m), 8.00(1H, d, J=16Hz), 8.60(1H, d, J=7Hz)
C
24H
27N
3The computational analysis value of O:
C77.18，H7.29，N11.25
Experimental value: C76.46, H7.19, N11.13
Mass spectrum: 373(M
+)
Embodiment 42
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-hydroxymethyl piperidines (trans-isomer(ide))
Fusing point: 143-145 ℃
Infrared spectra (whiteruss): 3320,1635,1575 1500Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.64(6H, wide), 2.70～3.33(1H, wide), 3.33～4.33(3H, m), 4.33-4.66(1H, wide), 6.75(1H, d, J=16Hz), and 6.78(1H, t, J=6Hz), 7.13～7.86(7H, m), 7.94(1H, d, J=16Hz), and 8.45) 1H, d, J=6Hz)
Mass spectrum: 361(M
+)
C
22H
23N
3O
21/2H
2The computational analysis value of O:
C71.33，H6.25，N11.34
Experimental value: C72.11, H6.31, N11.38
Embodiment 43
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-and the 4-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Fusing point: 89～93 ℃
3400,1640,1590,1530,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.93-2.30(7H, m), 2.47～3.28(2H, m), 3.40(2H, t, J=6Hz), 3.90～5.03(2H, m), 6.70(1H, d, J=15Hz), 6.90(1H, td, J=7Hz and 1Hz), 7.22～7.80(6H, m), 8.95(1H, d, J=15Hz), 8.53(1H, d, J=7Hz)
Mass spectrum: 375(M
+)
C
23H
25N
3The computational analysis value of O:
C73.58，H6.71，N11.19
Experimental value: C73.44, H6.70, N10.95
Embodiment 44
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethoxy carbonyl piperidines (trans-isomer(ide))
1725,1635,1585,1505Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.21(3H, t, J=8Hz), 1.33～2.00(6H, m), 2.00～2.50(1H, m), 3.00～3.50(1H, m), and 4.25(2H, q, J=8Hz), 5.25～5.60(1H, m)
C
24H
25N
3O
3C
2H
5The computational analysis value of O:
C69.47，H6.73，N9.35
Experimental value: C69.42, H6.70, N9.59
Mass spectrum: 403(M
+)
Embodiment 45
1-(2-methyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 133.5～134.5 ℃
1740,1620,1600,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.90(3H, t, J=7Hz), 1.33～2.00(8H, m), 1.80(3H, d, J=1Hz), 2.70～3.33(1H, m), 3.96～4.66(2H, m), 6.62(1H, S), 6.85(1H, td, J=7Hz and 1Hz), 7.13～7.70(5H, m), 7.80～8.03(2H, m), 8.57(1H, d, J=7Hz)
C
24H
27N
3The computational analysis value of O:
C77.18，H7.29，N11.25
Experimental value: C76.04, H7.34, N10.64
Mass spectrum: 373(M
+)
Embodiment 46
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2,2,6,6-tetramethyl piperidine (trans-isomer(ide))
Fusing point: 158～159 ℃
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.45(12H, S), 1.78(6H, S), and 6.46(1H, d, J=15Hz), and 6.72(1H, t, J=7Hz), 7.08～7.80(8H, m), and 8.48(1H, d, J=7Hz)
C
25H
29N
3The computational analysis value of O:
C77.49，H7.54，N10.84
Experimental value: C77.75, H7.49, N10.74
Embodiment 47
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-methoxymethyl tetramethyleneimine (trans-isomer(ide))
1700,1640,1590,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.77～2.15(4H, m), 3.33(3H, S), 3.20～3.72(2H, m),
4.00～4.60(1H is wide), 6.90(1H, td, J=8Hz and 1Hz), 7.20～7.90(8H, m), 8.02(1H, d, J=16Hz), and 8.57(1H, d, J=8Hz)
C
23H
25N
3O
2H
2The computational analysis value of O:
C70.20，H6.91，N10.06
Experimental value: C70.05, H6.69, N9.93
Mass spectrum: 375(M
+)
(α)
26.8 D=-70.44 ° (C=0.978, ethanol)
Embodiment 48
1-((2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2,4-pentadiene acyl group)-the 2-ethyl piperidine
1620,1580,1500Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.88(3H, t, J=6Hz), 1.10～2.00(8H, m), 2.50～3.33(1H, m), 3.66～5.00(2H, m), and 6.42(1H, d, J=15Hz), 6.66～7.94(11H, m), and 8.59(1H, d, J=7Hz)
C
25H
27N
3The analytical calculation value of O:
C77.89，H7.06，N10.90
Experimental value: C77.57, H6.95, N10.69
Embodiment 49
(2R)-1-(3-the 2-(3-pyridyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Fusing point: 137～139 ℃
3470,1620,1580Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.30～2.10(6H, m), 2.60～3.20(1H, m), 3.10～4.00(2H, m), 3.90～4.40(1H, m), 4.40～5.10(1H, m), 6.62(1H, d, J=16.0Hz) 6.87(1H, t, J=7.5Hz), 7.28(1H, t, J=7.5Hz), 7.38(1H, t, J=7.5Hz), 7.58～8.05(3H, m), 8.46(1H, d, J=7.5Hz), 8.64(1H, d, J=5.5Hz), 8.93(1H, S)
C
22H
24N
4O
2The computational analysis value:
C70.19，H6.43，N14.88
Experimental value: C70.13, H6.39, N14.85
Mass spectrum: 376(M
+)
Embodiment 50
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) propionyl)-the 2-ethyl piperidine
Infrared spectra (whiteruss): 1620,1520Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.60～1.00(3H, m), 1.20～1.90(7H, m), 2.27～2.83(4H, m), 3.10～3.67(3H, m), 4.40～4.64(1H, m), 6.60～8.90(8H, m), and 8.47(1H, d, J=7Hz)
C
23H
27N
3The computational analysis value of O:
C76.42，H7.53，N11.62
Experimental value: C74.94, H6.98, N11.22
Mass spectrum: 361(M
+)
Embodiment 51
N-benzyl-N-methyl-3-(2-phenylpyrazole is (1,5-a)-pyridin-3-yl also) acrylamide (trans-isomer(ide))
Fusing point: 118～119 ℃
Infrared spectra (whiteruss): 1610,1510, Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 3.05(3H, S), 4.64(2H, S), and 6.70(1H, d, J=15Hz), and 6.90(1H, t, J=7Hz), 7.10-8.00(12H, m), and 8.08(1H, d, J=15Hz), and 8.54(1H, d, J=8Hz)
C
24H
21N
3The computational analysis value of O:
C78.44，H5.76，N11.44
Experimental value: C78.01, H5.91, N11.36
Mass spectrum: 367(M
+)
Embodiment 52
3-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-3-azabicyclic (3,2,2) nonanes (trans-isomer(ide))
Fusing point: 113～115 ℃
1630,1580,1500Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.67(8H, m), 1.92～2.23(2H, m), 3.50～4.00(4H, m), 6.83(1H, d, J=15Hz), 6.90(1H, t, J=7.5Hz), 7.23～7.93(7H, m), 7.97(1H, d, J=15Hz), and 8.56(1H, d, J=7.5Hz)
C
24H
25N
3O computational analysis value:
C77.59，H6.78，N11.31
Experimental value: C77.57, H6.96, N11.32
Mass spectrum: 371(M
+)
Embodiment 53
7-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-7-azabicyclo (2,2,1) heptane (trans-isomer(ide))
Fusing point: 155.5～156.5 ℃
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.25～2.00(8H, m), 4.00～4.90(2H, wide), 6.52(1H, d, J=16Hz), and 6.90(1H, td, J=7Hz and 1Hz), 7.20～8.83(7H, m), and 7.95(1H, d, J=16Hz), and 8.56(1H, d, J=7Hz)
C
22H
21N
3The computational analysis value of O:
C76.94，H6.16，N12.24
Experimental value: C77.28, H6.05, N12.54
Mass spectrum: 343(M
+)
Embodiment 54
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl) perhydro--carotene 1H-azepines 1/2 fumarate (trans-isomer(ide))
Fusing point: 146～147 ℃
1685,1635,1580,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 1.33～1.90(8H, wide), 3.35～3.80(4H, m), 6.65(2H, S), 6.82(1H, d, J=15Hz), 7.13(1H, t, J=7Hz) 7.42～7.90(7H, m), 8.12(1H, d, J=8Hz), 8.90(1H, d, J=7Hz), 12.30～13.20(1H, wide)
C
24H
25N
3O
31/2H
2O computational analysis value:
C69.88，H6.59，N10.19
Experimental value: C70.39, H6.01, N9.99
Mass spectrum: 345(M
+)
Embodiment 55
1-(2-bromo-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-the 2-ethyl piperidine
Nucleus magnetic resonance (CDCl
3, δ): 0.93(3H, t, J=7.0Hz), 1.45～2.10(8H, m), 2.42～3.37(1H, m), 4.00～4.70(2H, m), 6.87(1H, td, J=7.0Hz and 2.0Hz), 7.67～7.95(8H, m), 8.52(1H, dd, J=6.5Hz and 1.0Hz)
Mass spectrum: 437,439(M
+)
Embodiment 56
Thionyl chloride (240 milligrams) is dropwise added 2-phenylpyrazole also (1,5-a) pyridine-3-carboxylic acid (compound (I)) (320 milligrams) and N, in dinethylformamide () the stirring the mixture in chloroform (10 milliliters), under reflux state, stirred four hours then.
Behind the cooling mixture, evaporate the chloride of acid that chloroform obtains compound (I) in a vacuum.
Triethylamine (338 milligrams) is joined under ice-cooled condition in the suspension of chloride of acid in methylene dichloride (10 milliliters) of compound (I); and in suspension, dropwise add the dichloromethane solution of 2-ethyl piperidine; under ice-cooled condition, stir the mixture, and at room temperature place and spend the night.
In mixture, add saturated sodium-chloride water solution (20 milliliters), use chloroform (20 milliliters) extraction subsequently.Extract is dry and evaporation in a vacuum on sal epsom.Resistates is gone up with chromatography and is separated at silica gel (8 gram), uses the chloroform give eluant, merges the cut that contains the purpose compound, obtains also (1,5-a) pyridin-3-yl carbonyl of 1-(2-phenylpyrazole after the evaporation in a vacuum)-2-ethyl piperidine (263 milligrams).
Fusing point: 182～183 ℃
1630,1600,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.69(3H, t, J=7.0Hz), 1.12～1.93(8H, m), 2.73～3.17(1H, m), 3.69～4.45(2H, m), 7.07(1H, td, J=7.0Hz and 2.0Hz), 7.29～8.00(7H, m), 8.86(1H, dd, J=7.0Hz and 1.0Hz)
C
21H
23N
3The computational analysis value of O:
C75.65，H6.95，N12.60
Experimental value: C75.75, H7.01, N12.66
Embodiment 57
With potassium hydroxide (0.5 gram) 1-(2-bromo-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-mixture of 2-ethyl piperidine (1.0 gram) in ethanol (10 milliliters) heated 1.5 hours under reflux state.
Evaporate ethanol in a vacuum, in resistates, add saturated sodium-chloride water solution (20 milliliters).Mixture evaporates after drying on the sal epsom with saturated sodium-chloride water solution washing (20 milliliters) in a vacuum with ethyl acetate (20 milliliters * 2) extraction, the extraction liquid of merging.Resistates carries out chromatography with the chloroform give eluant on silica gel separates; merge the cut that contains the purpose compound; evaporation obtains 1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl in a vacuum)-oily matter of 2-ethyl piperidine (0.71 gram)
2180,1600,1510Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.85(3H, t, J=7.0Hz), 1.30～2.00(8H, m), 2.40～3.43(1H, m), 4.15～4.85(2H, m), and 6.90(1H, td, J=7.0Hz and 2.0Hz), 7,17～8.33(7H, m), and 8.50(1H, d, J=7.0Hz)
Mass spectrum: 357(M
+)
Embodiment 58
Lindler catalyzer (21 milligrams) and quinoline (0.2 milliliter) are joined 1-(3-(2-phenylpyrazole also (1; 5-a)-pyridin-3-yl) propioloyl)-solution of 2-ethyl piperidine (410 milligrams) in ethyl acetate (10 milliliters) in, mixture stirs with hydrogen.
After filtering out catalyzer, evaporative removal ethyl acetate in a vacuum.Resistates separates with chromatography on silica gel, makes eluant with the mixture of normal hexane and chloroform (1: 1).Merge the cut contain the purpose compound, obtain 1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl after the evaporation in a vacuum)-oily matter of 2-ethyl piperidine (cis-isomeride) (156.3 milligrams).
1630,1600,1520Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.80(3H, t, J=7.0Hz), 1.10～2.00(8H, m), 2.30～3.20(1H, m), 3.70～4.83(2H, m), and 6.17(1H, d, J=12.5Hz), 6.57-8.03(9H, m), 8.48(1H, dd, J=7.0Hz and 1.0Hz)
Embodiment 59
Phosphine acyl acetic acid three ethyl (14.56 gram) is dropwise joined sodium hydride (60% under ice-cooled condition; 2.60 gram) in the suspension in tetrahydrofuran (THF) (100 milliliters); after stirring 1 hour at room temperature; in mixture, add 2-phenylpyrazole also (1; 5-a) pyridine-3-formaldehyde (11.10 gram) stirred 1 hour then at room temperature.
Reaction mixture is poured on the frozen water, use ethyl acetate extraction, extract washs with saturated sodium-chloride water solution, after drying on the sal epsom, evaporation obtains also (1,5-a) pyridin-3-yl of 3-(2-phenylpyrazole in a vacuum) ethyl propenoate (trans-isomer(ide)) (12.60 gram).
Fusing point: 130～131 ℃
1690,1615,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.30(3H, t, J=6.0Hz), and 4.27(2H, q, J=6.0Hz), and 6.30(1H, d, J=16.0Hz), and 6.88(1H, td, J=6.0Hz and 2.0Hz), 7.16～8.33(8H, m), 8.53(1H, dd, J=8.0Hz and 1.0Hz)
Following compound (embodiment 60 and 61) obtains according to the similar approach of embodiment 59.
Embodiment 60
3-(2-(3-pyridyl) pyrazolo (1,5-a) pyridin-3-yl)-ethyl propenoate (trans-isomer(ide))
Fusing point: 142～146 ℃
Infrared spectra (whiteruss): 1690,1620Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.15(3H, t, J=7.5Hz), 4.08(2H, q, J=7.5Hz), 6.10(1H, d, J=16.0Hz), 6.74(1H, t, J=7.5Hz), 7.03～7.40(2H, m), 7.57～7.94(3H, m), 7.78(1H, S), 7.57～7.94(3H, m), 8.35(1H, d, J=7.5Hz), 8.52(1H, d, J=4.5Hz)
Embodiment 61
(2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2,4-pentadienoic acid ethyl ester
Fusing point: 123.5～125.5 ℃
1705,1605,1500,1260,1235Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.30(3H, t, J=6Hz), and 4.23(2H, q, J=6Hz), and 5.89(1H, d, J=15Hz), and 6.98(1H, d, J=15Hz), 6.60～6.97(1H, m), 7.23～7.90(9H, m), and 8.55(1H, d, J=8Hz)
C
20H
18N
2O
2The computational analysis value:
C75.45，H5.70，N8.80
Experimental value: C75.87, H5.57, N8.90
Mass spectrum: 318(M
+)
Embodiment 62
In 7 ℃ and nitrogen atmosphere; with sodium hydride (60%; 110 milligrams) join 1-(2-diethoxy phosphoryl ethanoyl)-solution of 2-ethyl piperidine (0.80 gram) in tetrahydrofuran (THF) (5 milliliters) in; under 10 ℃ of conditions; with 4-methyl-2-phenylpyrazole also (1; 5-a) solution of pyridine-3-formaldehyde (0.50 gram) in tetrahydrofuran (THF) (5 milliliters) dropwise joins in the above-mentioned solution, at room temperature stirs then 1 hour.Behind the evaporating solvent, in residue, add saturated sodium-chloride water solution (20 milliliters) in a vacuum, and extract with ethyl acetate (20 milliliters * 2).The extract that merges, evaporates after drying on the sal epsom in a vacuum with saturated sodium-chloride water solution (20 milliliters) washing.Resistates is gone up and is carried out chromatographic separation with the chloroform give eluant at silica gel (20 gram); merge the cut that contains the purpose compound; obtain 1-(3-(4-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl after the evaporation in a vacuum)-oily matter of 2-ethyl piperidine (trans-isomer(ide)) (788 milligrams).
1630,1580,1540Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.71(3H, t, J=7.0Hz), 1.24～2.05(8H, m), 2.79(3H, S), 6.29(1H, d, J=16.0Hz), 6.74(1H, t, J=7.0Hz), 7.05(1H, d, J=7.0Hz), 7.24～7.93(5H, m), 8.24(1H, d, J=16.0Hz), 8.38(1H, d, J=7.0Hz)
Mass spectrum: 373(M
+)
Embodiment 63
Adopt general method with 1-(3-(4-methyl-2-phenylpyrazole also (1; 5-a) pyridin-3-yl)-acryl)-2-ethyl piperidine (trans-isomer(ide)) is converted into 1-(3-(4-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide)).
Fusing point: 124～126 ℃
1685,1620,1530Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.62(3H, t, J=7.0Hz) 1.06～1.90(8H, m), 3.43～4.43(2H, m), 6.24(1H, d, J=16.0Hz), 6.67(1H, S), 6.94(1H, t, J=7.0Hz) 7.24(1H, t, J=7.0Hz), 7.45～7.87(5H, m), 8.05(1H, d, J=16.0Hz), 8.67(1H, d, J=7.5Hz)
C
24H
27N
3O1/2C
4H
4O
4The computational analysis value:
C72.54，H6.56，N9.76
Experimental value: C71.65, H6.43, N9.52
Following compound (embodiment 64～79) obtains according to the similar approach of embodiment 62 and/or embodiment 63.
Embodiment 64
1-(3-(5-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Fusing point: 139～141 ℃
Infrared spectra (whiteruss): 1705,1640Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.82(3H, t, J=7.0Hz), 1.14-2.23(8H, m), 2.50(3H, S), 2.62～3.38(1H, m), 4.07～4.70(2H, m), 6.67(1H, S), 6.88～7.20(2H, m), 7.48～8.14(7H, m), 8.81(1H, d, J=7.0Hz)
C
24H
27N
3O1/2C
4H
4O
4The computational analysis value:
C68.69，H6.38，N8.58
Experimental value: C68.81, H6.37, N8.58
Embodiment 65
1-(3-(7-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (reaction isomer)
Fusing point: 95～97 ℃
Infrared spectra (whiteruss): 1620,1570,1535,1505Cm
-1Nucleus magnetic resonance (CDCl
3, δ): 0.87(3H, t, J=7.0Hz) 1.23～2.00(8H, m), 2.80(3H, S), 2.72～3.20(1H, m), 3.83～4.67(2H, m), 6.68(1H, d, J=16.0Hz), 6.77(1H, d, J=7.0Hz), 7.20(1H, d, J=8.0Hz), 7.37～7.83(6H, m), 8.00(1H, d, J=16.0Hz)
C
24H
27N
3The computational analysis value of O:
C77.18，H7.29，N11.25
Experimental value: C77.15, H7.18, N11.14
Embodiment 66
1-(3-the 2-(3-p-methoxy-phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 115-118 ℃
1635,1605,1575Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.80(3H, t, J=7.5Hz), 1.20～1.90(8H, m), 2.60～3.10(1H, m), 3.85(3H, S),
3.90～4.60（2H，m），6.90（1H，d，J＝1.0Hz），7.05～7.62（6H，m），7.76（1H，d，J＝16.0Hz），8.14（1H，d，J＝9.0Hz），8.87（1H，d，J＝7.5Hz）
C
24H
27N
3O
2The computational analysis value:
C74.01，H6.99，N10.79
Experimental value: C73.98, H6.88, N10.76
Embodiment 67
1-(3-the 2-(4-p-methoxy-phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1625,1610,1575Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, d): 0.77(3H, t, J=7.0Hz) 1.00～1.90(8H, m), 2.50～3.20(1H, m), 3.82(3H, S), 3.60～4.75(2H, m), 6.57～8.06(7H, m), and 8.50(1H, d, J=7Hz)
C
24H
27N
3O1/4H
2O computational analysis value:
C74.01，H6.99，N10.79
Experimental value: C73.09, H6.98, N10.47
Mass spectrum: 389(M
+)
Embodiment 68
1-(3-the 2-(2-chlorophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1580,1515Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.78(3H, t, J=7.0Hz) 1.22～1.93(8H, m), 2.51～3.23(1H, m), 3.50～4.72(2H, m), and 6.65(1H, d, J=16.0Hz), 6.77～7.93(8H, m), and 8.53(1H, d, J=7.0Hz)
Mass spectrum: 393(M
+)
Embodiment 69
1-(3-the 2-(4-chlorophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Fusing point: 136～140 ℃
1750,1635,1550,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.80(3H, t, J=7.0Hz) 1.30～1.90(8H, m), 2.70～3.20(1H, m), 3.93～4.67(2H, m), 6.57～7.96(8H, m), and 8.15(1H, d, J=8.0Hz) 8.84(1H, d, J=7.0Hz)
C
23H
24ClN
3O1/2C
4H
4O
4The analytical calculation value:
C66.44，H5.80，N9.30
Experimental value: C66.30, H5.65, N9.35
Mass spectrum: 392(M
+)
Embodiment 70
1-(3-the 2-(3-nitrophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Fusing point: 156～158 ℃
Infrared spectra (whiteruss): 1710,1635Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.74(3H, t, J=7.5Hz), 1.2～1.80(8H, m), 2.60～3.20(1H, m), 4.00～4.60(2H, m), 6.65(1H, S), 6.94(1H, d, J=16.0Hz) 7.13(1H, t, J=7.5Hz), 7.55(1H, t, J=7.5Hz), 7.70(1H, d, J=16.0Hz) 7.85(1H, t, J=7.5Hz), 8.12(2H, d, J=9.0Hz), 8.35(1H, d, J=9.0Hz) 8.45(1H, s), 8.28(1H, d, J=7.5Hz)
C
23H
24N
4O
31/2C
4H
4O
4The computational analysis value:
C64.92，H5.67，N12.11
Experimental value: C65.16, H5.65, N12.22
Embodiment 71
1-(3-the 2-(4-nitrophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 170～171 ℃
1635,1575,1510Cm infrared spectra (whiteruss):
-1Nucleus magnetic resonance (CDCl
3, δ): 0.82(3H, t, J=7.5Hz) 1.20～1.80(8H, m), 2.51～3.10(1H, m), 3.70～4.70(2H, m), and 6.73(1H, d, J=16.0Hz), 6.90(1H, t, J=7.5Hz), 7.33(1H, t, J=7.5Hz), 7.78(1H, d, J=7.5Hz), 7.88(1H, d, J=1.60Hz), 7.90(2H, d, J=9.0Hz) 8.33(2H, d, J=9.0Hz), 8.51(1H, d, J=7.5Hz)
C
23H
24N
4O
3The computational analysis value:
C68.30，H5.98，N13.85
Experimental value: C68.33, H5.96, N13.71
Embodiment 72
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-methacryloyl)-the 2-ethyl piperidine
Nucleus magnetic resonance (CDCl
3, δ): 0.50～1.10(3H, m), 1.08～2.30(11H, m), 2.33～3.36(1H, m), 3.36～4.20(1H, m),
4.20～5.06(1H, m), 6.14(1H, S), 6.80(1H, td, J=7Hz and 1Hz), 7.07～8.00(8H, m), and 8.50(1H, d, J=7Hz)
Mass spectrum: 373(M
+)
Embodiment 73
1-(3-(7-methoxyl group-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 122～123 ℃
1630,1580,1540,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.83(3H, t, J=7.0Hz), 1.25～2.02(8H, m), 2.57～3.15(2H, m), 3.95～4.60(2H, m), 4.15(3H, S), 6.22(1H, dd, J=6.0Hz and 3.0Hz), 6.60(1H, d, J=16.0Hz), 7.26～8.12(8H, m)
C
24H
27N
3O
2The computational analysis value:
C74.01，H6.99，N10.79
Experimental value: C74.15, H6.96, N10.83
Embodiment 74
1-(3-(4-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Fusing point: 132～133 ℃
Infrared spectra (whiteruss): 1680,1620Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.60(3H, t, J=7.0Hz), 1.0～1.80(8H, m), 6.25(1H, d, J=16.0Hz), 6.67(1H, S), and 7.05(1H, t, J=7.0Hz), 7.43～7.93(6H, m), 8.17(1H, d, J=16.0Hz), and 9.82(1H, d, J=7.0Hz)
C
23H
24ClN
3O1/2C
4H
4O
4The computational analysis value:
C66.44，H5.80，N9.30
Experimental value: C65.97, H5.75, N9.03
Embodiment 75
1-(3-(6-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
1630,1580,1505Cm infrared spectra (film):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.83(3H, t, J=7.0Hz), 1.37～1.87(8H, m), and 6.67(1H, d, J=16.0Hz), 7.15～8.05(8H, m), 8.53(1H, wide S)
Mass spectrum: 393(M
+)
Embodiment 76
1-(3-the 2-(2-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 131～133 ℃
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.89(3H, t, J=7.0Hz), 1.50～1.80(8H, m), 2.80～3.20(1H, m), 3.90～4.70(2H, m), 6.88(1H, d, J=7.0Hz), 6.97(1H, d, J=16.0Hz), 7.20～7.43(2H, m), 7.70～8.12(3H, m), 8.36(1H, d, J=16.0Hz), 8.51(1H, d, J=7.0Hz) 8.80(1H, d, J=6.0Hz)
C
22H
24N
4The computational analysis value of O:
C73.31，H6.71，N15.54
Experimental value: C73.50, H6.55, N15.50
Embodiment 77
(2S)-1-(3-the 2-(3-pyridyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Nucleus magnetic resonance (CDCl
3, δ): 0.82(3H, t, J=7.5Hz), 1.20～1.90(8H, m), 2.50～3.20(1H, m)
3.60～4.90（2H，m），6.65（1H，d，J＝16.0Hz），6.86（1H，t，J＝7.5Hz），7.23（1H，t，J＝5.0Hz），7.37（1H，t，J＝7.5Hz），7.73（1H，d，J＝7.5Hz）7.84（1H，d，J＝16.0Hz），8.00（1H，d，J＝6.0Hz），8.49（1H，d，J＝7.5Hz），8.63（1H，d，J＝5.0Hz），8.95（1H，S）
Mass spectrum: 360(M
+)
Embodiment 78
(2S)-1-(3-the 2-(3-pyridyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Fusing point: 106～109 ℃
1700,1635,1580,1560Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3-DMSO-d
6, δ): 0.85(3H, t, J=7.5Hz), 1.30～1.90(8H, m), 2.40～3.20(1H, m), 3.70～4.80(2H, m),
6.72（1H，d，J＝16.0Hz），6.77（2H，S），6.91（1H，t，J＝7.5Hz），7.35（1H，t，J＝7.5Hz），7.24-7.55（2H，m），7.80（1H，d，J＝7.5Hz），7.83（1H，d，J＝16.0Hz），8.04（1H，d，J＝7.5Hz），8.53（1H，d，J＝7.5Hz），8.66（1H，d，J＝5.0Hz），8.95（1H，S）
C
22H
24N
4O1/2C
4H
4O
4The computational analysis value:
C65.53，H5.92，N11.78
Experimental value: C64.43, H5.98, N11.50
Embodiment 79
1-(3-(2-sec.-propyl pyrazolo (1,5-a) pyridin-3-yl)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Fusing point: 36-38 ℃
Infrared spectra (whiteruss): 1620Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.95(3H, t, J=7.0Hz) 1.45(6H, d, J=7.0Hz), 1.46～2.30(8H, m), 2.77～3.37(2H, m),
3.57(1H, septet, J=7.0Hz), 4.25～4.97(2H, m), 6.82(1H, d, J=16.0Hz) 6.73～7.07(1H, m), 7.38(1H, td, J=7.0Hz and 1.0Hz), 7.80(1H, dd, J=7.0Hz and 1.0Hz), 8.05(1H, d, J=16.0Hz), 8.55(1H, dd, J=7.0Hz and 1.0Hz)
C
20H
27N
3The computational analysis value of O:
C73.81，H8.36，N12.91
Experimental value: C72.53, H8.19, N12.56
Embodiment 80
In 25～31 ℃ and nitrogen atmosphere; with 1-(2-diethoxy phosphoryl ethanoyl)-2-ethyl piperidine (0.80 gram) dropwise joins sodium hydride (60%; 0.17 gram) in the suspension in tetrahydrofuran (THF) (3 milliliters); then; in mixture, add the 2-(3-chlorophenyl in batches) pyrazolo (1,5-a) pyridine-3-carbonyl (0.80 gram).
After stirring 2 hours under 25～31 ℃, evaporate tetrahydrofuran (THF) in a vacuum.Add entry in resistates, use ethyl acetate extraction, extract evaporates after drying on the sal epsom in a vacuum with wet chemical (x2) and saturated sodium-chloride water solution (x2) washing.
Resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (22 gram), makes eluant with methylene dichloride and ethyl acetate (10: 1) mixture.The cut that will contain the purpose compound merges, and evaporation obtains 1-(3-{ 2-(3-chlorophenyl) pyrazolo (1,5-a) pyridin-3-yl in a vacuum } acryl)-2-ethyl piperidine (trans-isomer(ide)) (0.37 gram) xln.
Fusing point: 100～104 ℃
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3δ): 0.86(3H, t, J=8.0Hz), 1.30～1.90(8H, m), 2.60～3.20(1H, m), 3.80～4.70(2H, m), 6.65(1H, d, J=16.0Hz), 6.85(1H, t, J=7.5Hz), 7.15～7.75(6H, m), 7.88(1H, d, J=16.0Hz), 8.43(1H, d, J=7.5Hz)
C
23H
24ClN
3O computational analysis value:
C70.13，H6.14，N10.68
Experimental value: C70.37, H5.97, N10.81
Mass spectrum: 393(M
+)
Embodiment 81
With 1-(2-diethoxy phosphoryl ethanoyl)-solution of 2-ethyl piperidine (0.99 gram) in tetrahydrofuran (THF) (1.8 milliliters) dropwise joining under 23 to 25 ℃ in the suspension of sodium hydride (60%, 0.14 gram) in tetrahydrofuran (THF) (4.5 milliliters).After stirring 30 minutes under 24 ℃ of conditions, in mixture, add the 2-(4-pyridyl) pyrazolo (1,5-a) pyridine-3-formaldehyde (0.63 gram), at room temperature stirred 1 hour then.
Reaction mixture is poured in the wet chemical, with ethyl acetate (X2) extraction.Extraction liquid after the merging washs with saturated sodium-chloride water solution, after drying on the sal epsom, and evaporation in a vacuum.Resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (25 gram), makes eluant with the mixture of chloroform and methyl alcohol (100: 1).Merge the cut that contains the purpose compound, evaporation obtains xln in a vacuum.This crystal is recrystallization in the mixture of second alcohol and water (1: 1), obtains 1-(3-{ 2-(4-pyridyl) pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)) (0.38 gram).
Fusing point: 150～153 ℃
Infrared spectra (whiteruss): 1640,1605Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.77(3H, t, J=7.5Hz)
1.20～1.80（8H，m），2.50～3.20（1H，m），3.60～4.80（2H，m），6.65（1H，d，J＝16.0Hz），6.85（1H，t，J＝7.5Hz），7.26（1H，t，J＝7.5Hz）7.33～7.97（3H，m），7.85（1H，d，J＝16.0Hz），8.45（1H，d，J＝7.5Hz），8.67（1H，d，J＝5.0Hz）
C
22H
24N
4O computational analysis value:
C73.31，H6.71，N15.54
Experimental value: C73.65, H6.77, N15.39
Following compound (embodiment 82 and 83) is that the similarity method according to embodiment 8 makes.
Embodiment 82
3-(2-(3-pyridyl) pyrazolo (1,5-a) pyridin-3-yl)-vinylformic acid (trans-isomer(ide)).
Fusing point: 251～252 ℃
1680,1620,1600Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (trifluoroacetic acid, δ): 6.47(1H, d, J=15.0Hz),
7.25（1H，t，J＝6.5Hz），7.60～8.22（4H，m），8.70～9.15（4H，m）
Embodiment 83
(2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2, the 4-pentadienoic acid
Fusing point: 230～230.5 ℃
1690,1605,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 5.92(1H, d, J=15Hz) 6.93～7.87(10H, m), and 8.13(1H, d, J=8Hz), and 8.83(1H, d, J=8Hz)
Mass spectrum: 290(M
+)
Embodiment 84
The preparation method that employing is similar to embodiment 8 is by 3-(2-phenylpyrazole (1,5-a) pyridin-3-yl also) ethyl propenoate (trans-isomer(ide)) makes also (1,5-a) pyridin-3-yl of 3-(2-phenylpyrazole) vinylformic acid (trans-isomer(ide)).
The physical data of this compound is identical with the compound that embodiment 8 obtains.
Embodiment 85
The method that employing is similar to embodiment 7 and 8 from the 2-phenyl-pyrazole also (1,5-a) pyridine-3-formaldehyde obtain also (1,5-a) pyridin-3-yl of 2-methyl-3-(2-phenylpyrazole) vinylformic acid (trans-isomer(ide)).
Fusing point: 215-216 ℃
1700,1630,1520Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 1.80(3H, S), and 7.06(1H, td, J=7Hz and 1Hz), 7.33～7.90(8H, m), and 8.86(1H, d, J=7Hz)
Mass spectrum: 278(M
+)
Embodiment 86
Under 5～10 ℃, chloroform (5 milliliters) solution of bromine (1.65 gram) is dropwise joined also (1,5-a) pyridin-3-yl of 3-(2-phenyl-pyrazole) in chloroform (25 milliliters) solution of methyl acrylate (trans-isomer(ide)) (1.65 gram).
After stirring 2 hours 40 minutes at room temperature, evaporate chloroform in a vacuum.In the gained resistates, add 95% ethanol (15 milliliters) and potassium hydroxide (1.5 restrain), then under refluxad with mixture heating up 4.5 hours.
Evaporate ethanol in a vacuum, resistates is dissolved in the 1N aqueous sodium hydroxide solution.Filter out insolubles, filtrate is used 5% hcl acidifying.Collect the precipitation that forms with filtering, and water and methanol wash, obtain also (1.5-a) pyridin-3-yl of 2-bromo-3-(2-phenylpyrazole) acrylic acid xln (1.29 gram).
Fusing point: 172～178 ℃
Infrared spectra (whiteruss): 1685,1605Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 7.11(1H, td, J=7.0Hz and 1.0Hz), 7.37～7.93(7H, m), 8.38(1H, S), and 8.87(1H, d, J=7.0Hz)
C
16H
11BrN
2O
2The computational analysis value:
C56.00，H3.21，N8.17
Experimental value: C58.35, H3.90, N7.76
Embodiment 87
Under ice-cooled condition, thionyl chloride (0.38 milliliter) is dropwise joined also (1.5-a) pyridin-3-yl of 3-(2-phenylpyrazole) vinylformic acid (trans-isomer(ide)) (1.06 gram) and N, in dinethylformamide (2) the stirring the mixture in methylene dichloride (6 milliliters).After at room temperature stirring 1 hour, under ice-cooled condition, in stirring the mixture, dropwise add propyl carbinol.After at room temperature stirring 10 minutes, reaction mixture is poured on the frozen water (20 milliliters), is adjusted to alkalescence (PH12), and uses dichloromethane extraction.Extract water and saturated sodium-chloride water solution washing after drying on the sal epsom, are evaporated.
Resistates behind the recrystallization, obtains also (1.5-a) pyridin-3-yl of 3-(2-phenylpyrazole from the mixture of diisopropyl ether and normal hexane) n-butyl acrylate (trans-isomer(ide)) (1.08 gram).
Fusing point: 80～82 ℃
Infrared spectra (whiteruss): 1690,1620,1510Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.03(3H, t, J=7Hz), 1.27～1.96(4H, m), and 4.25(2H, t, J=7Hz) 6.33(1H, d, J=15Hz), 6.97
(1H, td, J=7Hz and 1Hz), 7.25～7.97(7H, m), and 8.00(1H, d, J=15Hz), and 8.60(1H, d, J=7Hz)
C
20H
20N
2O
2The computational analysis value:
C74.98，H6.29，N8.74
Experimental value: C75.11, H6.32, N8.69
Embodiment 88
Under ice-cooled condition; with 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-hydroxymethyl piperidines (trans-isomer(ide)) (0.30 gram) joins in the solution of stirring of tetrahydrofuran (THF) (2 milliliters) and sodium hydride (62.8%, 0.04 restrains).After 30 minutes,, in the solution that stirs, add the solution of the tetrahydrofuran (THF) (2 milliliters) of methyl iodide (0.14 gram) at 0 ℃.Reaction mixture at room temperature stirred 4 hours, was poured on then (20 milliliters) in the water, and is dry on sal epsom after chloroform (20 milliliters) extraction, and evaporates in a vacuum.Resistates is gone up and is carried out chromatographic separation with the chloroform give eluant at silica gel (20 gram); merge the cut that contains the purpose compound; after the evaporation, obtain 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl in a vacuum)-oily matter of 2-methoxy methyl phenylpiperidines (trans-isomer(ide)) (0.30 gram).
Infrared spectra (whiteruss): 1640,1590,1440,1415Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.15～1.80(6H, m), 2.35～3.20(1H, wide), 3.40(3H, S), 3.90～4.80(2H, wide), 6.70(1H, d, J=16Hz), 6.78(1H, td, J=7Hz and 1Hz), 7.00～7.77(7H, m), 7.85(1H, d, J=16Hz), 8.45(1H, d, J=7Hz)
Mass spectrum: 375(M
+)
Embodiment 89
The method that employing is similar to embodiment 88 obtains 1-(3-(2-phenylpyrazole (1.5-a) pyridin-3-yl) acryl-2-(2-methoxy ethyl) piperidines (trans-isomer(ide)).
Fusing point: 139～140 ℃
Infrared spectra (whiteruss): 1635,1590,1510Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.40～2.20(9H, m), 2.30～3.10(1H, m), 3.30(3H, S),
3.95～5.05（2H，m），6.75～8.18（10H，m），8.55（1H，d，J＝7Hz）
C
24H
27N
3O
2The computational analysis value:
C74.01，H6.99，N10.79
Experimental value: C73.79, H6.51, N10.69
Mass spectrum: 389(M
+)
Embodiment 90
At room temperature; with 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-hydroxymethyl piperidines (trans-isomer(ide)) (0.50 gram) joins in the stirred solution of pyridine (5 milliliters) of acetic anhydride (0.16 gram), and at room temperature stirred 3 hours.In reaction mixture, add ethyl acetate, and use the 1N aqueous sodium hydroxide solution, water and saturated sodium-chloride water solution washing, dry on sal epsom then, evaporate in a vacuum.Resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (50 gram), makes eluant with the mixture of chloroform and acetone (20: 1).Merge the cut contain the purpose compound, obtain 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl through vacuum-evaporation)-oily matter of 2-acetoxy-methyl piperidines (trans-isomer(ide)) (0.35 gram).
Infrared spectra (whiteruss): 1740,1640,1590Cm
-1Nucleus magnetic resonance (CDCl
3, δ): 1.30～2.00(8H, wide), 2.02(3H, S), 2.65～3.15(1H, m), 3.90～4.90(2H, m), 6.73(1H, d, J=18Hz), 6.94(1H, dd, J=7.5Hz and 1.5Hz), 7.23～7.85(7H, m), 7.97(1H, d, J=18Hz), 8.53(1H, d, J=7.5Hz)
Mass spectrum: 403(M
+)
Embodiment 91
The method that employing is similar to embodiment 90 obtains 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-the 2-(2-acetoxyl group) piperidines (trans-isomer(ide)).
Infrared spectra (trichloromethane: 1725,1635,1585,1515Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.00～2.36(7H, m), 1.90(3H, S), 2.48～3.30(1H, wide), 4.02(2H, t, J=6Hz), 4.4～5.0(1H, wide), 6.65(1H, d, J=16Hz), and 6.83(1H, td, J=6Hz and 1Hz), 7.18～7.80
（7H，m），7.92（1H，d，J＝16Hz），8.50（1H，d，J＝6Hz）
C
25H
27N
3O
31/2H
2O computational analysis value:
C70.40，H6.85，N9.85
Experimental value: C70.96, H6.59, N9.71
Mass spectrum: 417(M
+)
Embodiment 92
With 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-ethoxy carbonyl piperidines (reaction isomer) (0.50 gram) and the mixture reflux of 1N aqueous sodium hydroxide solution (5 milliliters) in methyl alcohol (5 milliliters) 3 hours.After reaction mixture evaporates methyl alcohol, with 10% hydrochloric acid neutralization and use chloroform extraction.Extraction liquid washs with saturated sodium-chloride water solution, and is dry on sal epsom, and evaporation in a vacuum.Resistates is gone up and is carried out chromatographic separation with the chloroform give eluant at silica gel (20 gram); merge the cut that contains the purpose compound, after vacuum-evaporation, obtain 1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl) piperidines-2-carboxylic acid (trans-isomer(ide)) (0.26 gram) oily matter.
Infrared spectra (whiteruss): 3350,1750,1630,1560,1510Cm
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 1.07(3H, t, J=7Hz) 1.20～1.85(6H, wide), 2.00～2.45(1H is wide), 3.47(2H, q, J=7Hz), 3.90～4.75(1H is wide) 4.75～5.30(1H, m), 6.93(1H, d, J=15Hz), 7.12(1H, t, J=7Hz), 7.35-8.00(7H, m), 8.18(1H, d, J=7Hz), 8.80(1H, d, J=7Hz)
C
22H
21N
3O
3H
2The computational analysis value of O:
C67.16，H5.89，N10.68
Experimental value: C66.59, H6.01, N9.94
Mass spectrum: 375(M
+)
Embodiment 93
Under 45 ℃, with 1-(3-{ 2-(3-nitrophenyl) pyrazolo (1.5-a) pyridin-3-yl } acryl)-solution of 2-ethyl piperidine (trans-isomer(ide)) (2.00 gram) in ethanol (10 milliliters) dropwise joins iron powder (0.83 gram) and ammonium chloride (0.08 restrains) in the stirred mixture of ethanol (20 milliliters) and water (10 milliliters).Reaction mixture stirred 3 hours 20 minutes at 69 ℃.
Filter out undissolved inorganics, in a vacuum evaporating solvent.Resistates is recrystallization in the mixture of ethanol and ethyl acetate (1: 1), obtains 1-(3-{ 2-(3-aminophenyl) pyrazolo (1.5-a) pyridin-3-yl } acryl)-xln of 2-ethyl piperidine (trans-isomer(ide)) (1.36 gram).
Fusing point: 150～151 ℃
Infrared spectra (whiteruss): 3410,3340,3240,1635,1605Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.82(3H, t, J=7.5Hz) 1.20～1.80(8H, m), 2.50～3.50(2H, m), 3.80～4.70(2H, m), 6.60～7.40(7H, m), 7.74(1H, d, J=9.0Hz), 7.93(1H, d, J=16.0Hz), 8.49(1H, d, J=7.5Hz)
C
23H
26N
4The computational analysis value of O:
C73：77，H，7.00，N14.96
Experimental value: C73.37, H6.87, N14.80
Mass spectrum: 374(M
+)
Embodiment 94
The preparation method that employing is similar to embodiment 93 obtains 1-(3-{ 2-(4-aminophenyl) pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)).
Infrared spectra (whiteruss): 3335,3220,1635,1605,1580Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.85(3H, t, J=7.5Hz) 1.30～1.90(8H, m), 2.50～3.10(1H, m), 3.83(1H, wide S), 3.90～4.70(2H, m), 6.60～6.90(3H, m), 7.25(1H, t, J=7.5Hz), 7.42～7.80(3H, m), 7.95(1H, d, J=16.0Hz), 8.48(1H, d, J=7.5Hz)
C
23H
26N
4The computational analysis value of O:
C73.77，H7.00，N14.96
Experimental value: C72.87, H7.35, N14.69
Mass spectrum: 374(M
+)
Embodiment 95
With 1-(3-{ 2-(3-aminophenyl) pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)) (0.80 gram) and the mixture of acetic anhydride (0.21 milliliter) in toluene (8 milliliters) heated 45 minutes at 75～80 ℃.
Evaporate solvent in a vacuum, in resistates, add entry after, use dichloromethane extraction.Extraction liquid after the merging washs with saturated sodium-chloride water solution; after dry on the sal epsom and vacuum-evaporation, obtain 1-(3-{ 2-(3-acetylamino phenyl) pyrazolo (1.5-a) pyridin-3-yl }-acryl)-xln of 2-ethyl piperidine (trans-isomer(ide)) (0.33 restrains).
Fusing point: 225～231 ℃
Infrared spectra (whiteruss): 3380,1685,1635Cm
-1
Nucleus magnetic resonance (CDCl
3: DMSO=1: 1, δ): 0.80(3H, t, J=7.5Hz), 1.20～1.90(8H, m), 2.05(3H, S), 2.60～3.20(1H, m), 3.90～4.60(2H, m), 6.80(1H, d, J=16.0Hz) 7.02(1H, t, J=7.5Hz), 7.20-7.56(3H, m), 7.60～8.10(4H, m) 8.67(1H, d, J=7.5Hz), 10.00(1H, S)
C
25H
28N
4O
2The computational analysis value:
C72.09，H6.78，N13.45
Experimental value: C71.49, H6.48, N13.33
Embodiment 96
The method that employing is similar to embodiment 95 makes 1-(3-{ 2-(4-acetylamino phenyl) pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)).
3250,1685,1635,1595Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.37(3H, t, J=7.5Hz), 1.10～1.80(8H, m), 2.03(3H, S), 2.60～3.10(1H, m), 3.20～4.60(2H, m), 6.70～7.90(8H, m), and 8.09(1H, d, J=9.0Hz)
Mass spectrum: 416(M
+)
Embodiment 97
Under ice-cooled condition; methylsulfonyl chloride (0.59 gram) is dropwise joined 1-(3-{ 2-(3-aminophenyl) pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)) (1.20 gram) and triethylamine (0.52 restrains) be in the stirred solution of methylene dichloride (7.2 milliliters).
After at room temperature stirring 6 hours, reaction mixture washes twice with water, and is dry on sal epsom after saturated sodium-chloride washing once, and evaporation in a vacuum.Resistates is gone up and is carried out chromatographic separation with the chloroform give elutriant at silica gel (22 gram); merge the cut that contains the purpose compound; obtain 1-(3-{ 2-(3-methanesulfonamido phenyl)-pyrazolo (1,5-a) pyridin-3-yl through vacuum-evaporation } acryl)-xln of 2-ethyl piperidine (trans-isomer(ide)) (0.36 gram).
Fusing point: 188～190 ℃
3080,1635,1610Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.75(3H, t, J=7.5Hz), 1.20～1.80(8H, m), 2.60～3.20(1H, m), 3.06(3H, S), 3.90～4.70(2H, m), 6.92(1H, d, J=16.0Hz), 7.10(1H, t, J=7.5Hz), 7.17～7.66(5H, m), 7.73(1H, d, J=16.0Hz), 8.12(1H, d, J=9.0Hz), 8.87(1H, d, J=7.5Hz), 10.01(1H, S)
C
24H
28N
4O
3The computational analysis value of S:
C63.69，H6.24，N12.38
Experimental value: C63.52, H6.44, N12.29
Mass spectrum: 452(M
+)
Embodiment 98
Under ice-cooled condition; methyl-chloroformate (0.40 gram) is dropwise joined 1-(3-{ 2-(3-aminophenyl) pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide)) (1.20 gram) and the stirred solution of triethylamine (0.44 restrains) in methylene dichloride (7.2 milliliters) in.
After at room temperature stirring 6 hours, reaction mixture is poured on the wet chemical, uses ethyl acetate extraction.After extraction liquid water and the saturated sodium-chloride water solution washing; dry on sal epsom; obtain 1-(3-{ 2-(3-methoxycarbonyl aminophenyl) pyrazolo (1,5-a) pyridin-3-yl through vacuum-evaporation }-acryl)-xln of 2-ethyl piperidine (trans-isomer(ide)) (0.31 gram).
Fusing point: 143～145 ℃
3260,1725,1640Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 0.73(3H, t, J=7.5Hz), 1.20～1.80(8H, m), 2.60～3.10(1H, m), 3.65(3H, S), 3.80～4.60(2H, m), and 6.85(1H, d, J=16.0Hz), and 7.08(1H, t, J=7.5Hz),
7.30（1H，d，J＝7.5Hz），7.33～7.70（4H，m），7.80（1H，d，J＝2.0Hz），8.10（1H，d，J＝9.0Hz），8.80（1H，d，J＝7.5Hz），9.84（1H，S）
C
25H
28N
4O
3The computational analysis value:
C69.42，H6.52，N12.95
Experimental value: C69.18, H6.57, N12.87
Mass spectrum: 432(M
+)
Embodiment 99
At room temperature; with methyl iodide (0.84 gram) at N; solution in the N-dimethylformamide (2 milliliters) dropwise is added to 1-(3-{ 2-(3-aminophenyl) pyrazolo (1; 5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide)) (1.5 gram) and powdered salt of wormwood (0.28 restrains) is at N, in the stirred solution in the N-dimethylformamide (10 milliliters).After at room temperature stirring 2 hours 50 minutes, reaction mixture is poured in the water, used ethyl acetate extraction.Extraction liquid water and saturated sodium-chloride water solution washing, after drying on the sal epsom, evaporation in a vacuum.Resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (36 gram).Mixture with methylene dichloride and acetonitrile (5: 1) is made eluant.The cut that will contain primary product merges, and obtains 1-(3-{ 2-(3-methylamino phenyl) pyrazolo (1,5-a) pyridin-3-yl through vacuum-evaporation } acryl)-2-ethyl piperidine (trans-isomer(ide)) (0.21 gram) xln.
Fusing point: 135～141 ℃
3500,1635,1580,1510Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.78(3H, t, J=7.5Hz), 1.20～1.80(8H, m), 2.84(3H, S), 2.60～3.20(1H, m), 3.70～4.70(2H, m), 6.68(1H, d, J=16.0Hz) 6.68～7.08(4H, m), 7.272H, t, J=7.5Hz), 7.72(1H, d, J=9.0Hz), 7.94(1H, d, J=16.0Hz) 8.49(1H, d, J=7.5Hz)
C
24H
28N
4The computational analysis value of O:
C74.20，H7.26，N14.42
Experimental value: C74.07, H7.45, N14.30
Merge the cut contain secondary product, after vacuum-evaporation, obtain 1-(3-{ 2-(3-dimethylaminophenyl) pyrazolo (1.5-a) pyridin-3-yl acryl)-xln of 2-ethyl piperidine (trans-isomer(ide)) (0.18 gram).
Fusing point: 180～184 ℃
Infrared spectra (whiteruss): 1640,1600Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.82(3H, t, J=7.5Hz),
2.60～3.10（1H，m），3.70～4.60（2H，m）6.67（1H，d，J＝16.0Hz），6.75～7.12（4H，m），7.28（1H，t，J＝7.5Hz），7.78（1H，d，J＝9.0Hz），7.95（1H，d，J＝16.0Hz），8.53（1H，d，J＝7.5Hz）
C
25H
30N
4The computational analysis value of O:
C74.60，H7.51，N13.92
Experimental value: C74.18, H6.87, N14.20
Mass spectrum: 402(M
+)
Following compound (embodiment 100 to 131) adopts the preparation method who is similar to embodiment 22 to make.
Embodiment 100
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (cis-isomeride)
Infrared spectra (film): 1630,1600,1520Cm
-1
Embodiment 101
1-(3-(4-methyl-2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (film): 1630,1580,1540Cm
-1
Embodiment 102
1-(3-(5-methyl-2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1705,1640Cm
-1
Embodiment 103
1-(3-(7-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
1620,1570,1535,1505Cm infrared spectra (whiteruss):
-1
Embodiment 104
1-(3-the 2-(3-p-methoxy-phenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1605,1575Cm infrared spectra (whiteruss):
-1
Embodiment 105
1-(3-the 2-(4-p-methoxy-phenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1625,1610,1575Cm infrared spectra (trichloromethane):
-1
Embodiment 106
1-(3-the 2-(2-chlorophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1580,1515Cm infrared spectra (film):
-1
Embodiment 107
1-(3-the 2-(4-chlorophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
1705,1635,1550,1510Cm infrared spectra (whiteruss):
-1
Embodiment 108
1-(3-the 2-(3-nitrophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1710,1635Cm
-1
Embodiment 109
1-(3-the 2-(4-nitrophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1575,1510Cm infrared spectra (whiteruss):
-1
Embodiment 110
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-methacryloyl)-the 2-ethyl piperidine
Mass spectrum: 373(M
+)
Embodiment 111
1-(3-(7-methoxyl group-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
1630,1580,1540,1510Cm infrared spectra (whiteruss):
-1
Embodiment 112
1-(3-(4-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1680,1620Cm
-1
Embodiment 113
1-(3-(6-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
1630,1580,1505Cm infrared spectra (film):
-1
Embodiment 114
1-(3-the 2-(2-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Embodiment 115
(2S)-1-(3-the 2-(3-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Mass spectrum: 360(M
+)
Embodiment 116
1-(3-(2-sec.-propyl pyrazolo (1,5-a) pyridin-3-yl)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1620Cm
-1
Embodiment 117
1-(3-the 2-(3-chlorophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 118
1-(3-the 2-(4-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1605Cm
-1
Embodiment 119
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-methoxy methyl phenylpiperidines (trans-isomer(ide))
1640,1590,1510,1440,1415Cm infrared spectra (whiteruss):
-1
Embodiment 120
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and the 2-(2-methoxy ethyl) piperidines (trans-isomer(ide))
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Embodiment 121
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-acetoxy-methyl piperidines (trans-isomer(ide))
1740,1640,1590Cm infrared spectra (trichloromethane):
-1
Embodiment 122
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and 2-(2-acetoxyl group ethyl) piperidines (trans-isomer(ide))
1725,1635,1585,1515Cm infrared spectra (trichloromethane):
-1
Embodiment 123
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-piperidines-2-carboxylic acid (trans-isomer(ide))
3350,1750,1630,1560,1510Cm infrared spectra (whiteruss):
-1
Embodiment 124
1-(3-the 2-(3-aminophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
3410,3340,3240,1635,1605Cm infrared spectra (whiteruss):
-1
Embodiment 125
1-(3-the 2-(4-aminophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
3335,3220,1635,1605,1580Cm infrared spectra (whiteruss):
-1
Embodiment 126
1-(3-the 2-(3-acetylamino phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3380,1685,1635Cm infrared spectra (whiteruss):
-1
Embodiment 127
1-(3-the 2-(4-acetylamino phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3250,1685,1635 1595Cm
-1
Embodiment 128
1-(3-2-(3-methanesulfonamido phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3080,1635,1610Cm infrared spectra (whiteruss):
-1
Embodiment 129
1-(3-2-(3-methoxycarbonyl aminophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3260,1725,1640Cm infrared spectra (whiteruss):
-1
Embodiment 130
1-(3-2-(3-methylamino phenyl) and pyrazolo (1,5-a)-pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3500,1635,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 131
1-(3-the 2-(3-dimethylaminophenyl) and pyrazolo (1,5-a)-pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1600Cm
-1
Employing is similar to embodiment 62(and embodiment 63) method be prepared as follows compound (embodiment 132 to 174).
Embodiment 132
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
1705,1635,1580,1540,1510Cm infrared spectra (whiteruss):
-1
Embodiment 133
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-tetramethyleneimine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1590Cm
-1
Embodiment 134
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 1630,1580Cm
-1
Embodiment 135
4-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-morpholine (trans-isomer(ide))
Infrared spectra (whiteruss): 1625,1580Cm
-1
Embodiment 136
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-4-methylpiperazine hydrochloride (trans-isomer(ide))
2400,1650,1580,1500Cm infrared spectra (whiteruss):
-1
Embodiment 137
N-methyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acrylamide (trans-isomer(ide))
3275,1640,1605Cm infrared spectra (whiteruss):
-1
Embodiment 138
N-sec.-propyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acrylamide (trans-isomer(ide))
3275,1640,1600Cm infrared spectra (whiteruss):
-1
Embodiment 139
N, N-dimethyl-3-(3-phenylpyrazole be (1,5-a) pyridin-3-yl also)-acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1590Cm
-1
Embodiment 140
N-(three rings (3,3,1,1
3.7) last of the ten Heavenly stems-the 1-yl)-3-(2-phenylpyrazole (1,5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
3280,1650,1590,1535,1500Cm infrared spectra (whiteruss):
-1
Embodiment 141
(2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
2930,2860,1635,1585Cm infrared spectra (film):
-1
Embodiment 142
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
2930,2860,1635,1585Cm infrared spectra:
-1
Embodiment 143
(2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3350,1640,1575,1520Cm infrared spectra (whiteruss):
-1
Embodiment 144
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3330,1635,1570,1520Cm infrared spectra (trichloromethane):
-1
Embodiment 145
(2RS)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3280,1625,1560,1510Cm infrared spectra (whiteruss):
-1
Embodiment 146
N, N-diethyl-3-(2-phenylpyrazole be (1,5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
1640,1595,1520Cm infrared spectra (trichloromethane):
-1
Embodiment 147
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-pipecoline (trans-isomer(ide))
1640,1590,1515Cm infrared spectra (trichloromethane):
-1
Embodiment 148
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-propyl group piperidines (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 149
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-hydroxymethyl piperidines (trans-isomer(ide))
3320,1635,1575,1500Cm infrared spectra (whiteruss):
-1
Embodiment 150
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and the 4-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3400,1640,1590,1530,1510Cm infrared spectra (whiteruss):
-1
Embodiment 151
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethoxy carbonyl piperidines (trans-isomer(ide))
1725,1635,1585,1505Cm infrared spectra (film):
-1
Embodiment 152
1-(2-methyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
1740,1620,1600,1520Cm infrared spectra (whiteruss):
-1
Embodiment 153
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2,2,6,6-tetramethyl piperidine (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 154
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-methoxymethyl tetramethyleneimine (trans-isomer(ide))
1700,1640,1590,1520Cm infrared spectra (whiteruss):
-1
Embodiment 155
1-((2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2,4-pentadiene acyl group)-the 2-ethyl piperidine
1620,1580,1500Cm infrared spectra (whiteruss):
-1
Embodiment 156
(2R)-1-(3-the 2-(3-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 3470,1620,1580Cm
-1
Embodiment 157
N-benzyl-N-methyl-3-(2-phenylpyrazole is (1,5-a)-pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 1610,1510Cm
-1
Embodiment 158
3-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-azabicyclo (3,2,2) nonanes (trans-isomer(ide))
Infrared spectra (whiteruss): 1630,1580,1500Cm
-1
Embodiment 159
7-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-7-azabicyclo (2,2,1) heptane (trans-isomer(ide))
Infrared spectra (whiteruss): 1635,1590,1510Cm
-1
Embodiment 160
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-perhydro-1H-azepines 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1685,1635,1580,1520Cm
-1
Embodiment 161
The 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-n-butyl acrylate (trans-isomer(ide))
Infrared spectra (whiteruss): 1690,1620,1510Cm
-1
Embodiment 162
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-methoxy methyl phenylpiperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1590,1510,1440,1415Cm
-1
Embodiment 163
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-and the 2-(2-methoxy ethyl) piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 1635,1590,1510Cm
-1
Embodiment 164
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-acetoxy-methyl piperidines (trans-isomer(ide))
Infrared spectra (trichloromethane): 1740,1640,1590Cm
-1
Embodiment 165
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-and 2-(2-acetoxyl group ethyl) piperidines (trans-isomer(ide))
Infrared spectra (trichloromethane): 1725,1635,1585 1515Cm
-1
Embodiment 166
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-piperidines-2-carboxylic acid (trans-isomer(ide))
Infrared spectra (whiteruss): 3350,1750,1630,1560,1510Cm
-1
Embodiment 167
1-(3-the 2-(3-aminophenyl) pyrazolo (1.5-a) pyridine-2-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3410,3340,3,240 1635,1605Cm
-1
Embodiment 168
1-(3-the 2-(4-aminophenyl) pyrazolo (1.5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3335,3220,1635,1605,1580Cm
-1
Embodiment 169
1-(3-the 2-(3-acetylamino phenyl) and pyrido (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3380,1685,1635Cm
-1
Embodiment 170
1-(3-the 2-(4-acetylamino phenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3250,1685,1635 1595Cm
-1
Embodiment 171
1-(3-2-(3-methanesulfonamido phenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3080,1635,1610Cm
-1
Embodiment 172
1-(3-2-(3-methoxycarbonyl aminophenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3260,1725,1640Cm
-1
Embodiment 173
1-(3 2-(3-methylamino phenyl) and pyrazolo (1.5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 3500,1635,1580,1510Cm
-1
Embodiment 174
1-(3-the 2-(3-dimethylaminophenyl) and pyrazolo (1.5-a)-pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1600Cm
-1
The method that employing is similar to embodiment 25 makes following compound (embodiment 175～238).
Embodiment 175
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1705,1635,1580,1540,1510Cm
-1
Embodiment 176
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-tetramethyleneimine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1590Cm
-1
Embodiment 177
1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 1630,1580Cm
-1
Embodiment 178
4-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-morpholine (trans-isomer(ide))
Infrared spectra (whiteruss): 1625,1580Cm
-1
Embodiment 179
N-methyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 3275,1640,1605Cm
-1
Embodiment 180
N-sec.-propyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 3275,1640,1600Cm
-1
Embodiment 181
N, N-dimethyl-3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1590Cm
-1
Embodiment 182
N-(three rings (3,3,1,1
3.7) caprinoyl-1-yl)-3-(2-phenylpyrazole (1.5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 3280,1650,1,590 1535,1500Cm
-1
Embodiment 183
(2R)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (film): 2930,2860,1635,1585Cm
-1
Embodiment 184
(2S)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (film): 2930,2860,1635 1585Cm
-1
Embodiment 185
(2R)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also)-acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 3350,1640,1575 1520Cm
-1
Embodiment 186
(2S)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Infrared spectra (trichloromethane): 3330,1635,1570 1520Cm
-1
Embodiment 187
(2RS)-1-(the 3-(2-phenylpyrazole is (1.5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
Infrared spectra (whiteruss): 3280,1625,1560 1510Cm
-1
Embodiment 188
N, N-diethyl-3-(2-phenylpyrazole is (1.5-a) pyridine-3-yl also)-acrylamide (trans-isomer(ide))
1640,1595,1520Cm infrared spectra (trichloromethane):
-1
Embodiment 189
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-pipecoline (trans-isomer(ide))
1640,1590,1515Cm infrared spectra (trichloromethane):
-1
Embodiment 190
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-propyl group piperidines (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 191
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-hydroxymethyl piperidines (trans-isomer(ide))
3320,1635,1575,1500Cm infrared spectra (whiteruss):
-1
Embodiment 192
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and the 4-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3400,1640,1590,1530,1510Cm infrared spectra (whiteruss):
-1
Embodiment 193
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethoxy carbonyl piperidines (trans-isomer(ide))
1725,1635,1585,1505Cm infrared spectra (film):
-1
Embodiment 194
1-(2-methyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
1740,1620,1600,1520Cm infrared spectra (whiteruss):
-1
Embodiment 195
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2,2,6,6-tetramethyl piperidine (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 196
(2S)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-methoxymethyl tetramethyleneimine (trans-isomer(ide))
1700,1640,1590,1520Cm infrared spectra (whiteruss):
-1
Embodiment 197
1-((2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2,4-pentadiene acyl group)-the 2-ethyl piperidine
1620,1580,1500Cm infrared spectra (whiteruss):
-1
Embodiment 198
(2R)-1-(3-the 2-(3-pyridyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-the 2-(2-hydroxyethyl) piperidines (trans-isomer(ide))
3470,1620,1580Cm infrared spectra (whiteruss):
-1
Embodiment 199
N-benzyl-N-methyl-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acrylamide (trans-isomer(ide))
Infrared spectra (whiteruss): 1610,1510Cm
-1
Embodiment 200
3-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-3-azabicyclo (3,2,2) nonanes (trans-isomer(ide))
1630,1580,1500Cm infrared spectra (whiteruss):
-1
Embodiment 201
7-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-7-azabicyclo (2,2,1) heptane (trans-isomer(ide))
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Embodiment 202
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-perhydro--carotene 1H-azepines 1/2 fumarate (trans-isomer(ide))
1685,1635,1580,1520Cm infrared spectra (whiteruss):
-1
Embodiment 203
1-(2-bromo-3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-the 2-ethyl piperidine
Mass spectrum: 437,439(M
+)
Embodiment 204
3-(2-(3-pyridyl) pyrazolo (1,5-a) pyridin-3-yl)-ethyl propenoate (trans-isomer(ide))
Infrared spectra (whiteruss): 1690,1620Cm
-1
Embodiment 205
(2E, 4E)-5-(2-phenylpyrazole (1,5-a) pyridin-3-yl also)-2,4 pentadienoic acid ethyl esters
1705,1605,1500,1260,1235Cm infrared spectra (whiteruss):
-1
Embodiment 206
1-(3-(4-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
1630,1580,1540Cm infrared spectra (film):
-1
Embodiment 207
1-(3-(5-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1705,1640Cm
-1
Embodiment 208
1-(3-(7-methyl-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
1620,1570,1535,1505Cm infrared spectra (whiteruss):
-1
Embodiment 209
1-(3-the 2-(3-p-methoxy-phenyl) pyrazolo (1,5-a) pyridin-3-yl)-acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1605,1575Cm infrared spectra (whiteruss):
-1
Embodiment 210
1-(3-the 2-(4-p-methoxy-phenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
1625,1610,1575Cm infrared spectra (trichloromethane):
-1
Embodiment 211
1-(3-the 2-(2-chlorophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1580,1515Cm infrared spectra (film):
-1
Embodiment 212
1-(3-the 2-(4-chlorophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
1705,1635,1550,1510Cm infrared spectra (whiteruss):
-1
Embodiment 213
1-(3-the 2-(3-nitrophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1710,1635Cm
-1
Embodiment 214
1-(3-the 2-(4-nitrophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1575,1510Cm infrared spectra (whiteruss):
-1
Embodiment 215
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-methacryloyl)-2-ethyl piperidine (trans-isomer(ide))
Mass spectrum: 373(M
+)
Embodiment 216
1-(3-(7-methoxyl group-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine (trans-isomer(ide))
1630,1580,1540,1510Cm infrared spectra (whiteruss):
-1
Embodiment 217
1-(3-(4-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-ethyl piperidine 1/2 fumarate (trans-isomer(ide))
Infrared spectra (whiteruss): 1680,1620cm
-1
Embodiment 218
1-(3-(6-chloro-2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (film) 1630,1580,1505Cm
-1
Embodiment 219
1-(3-the 2-(2-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Embodiment 220
(2S)-1-(3-the 2-(3-pyridyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Mass spectrum: 360(M
+)
Embodiment 221
1-(3-(2-sec.-propyl pyrazolo (1,5-a) pyridin-3-yl) acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1620Cm
-1
Embodiment 222
1-(3-the 2-(3-chlorophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
1640,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 223
1-(3-the 2-(4-pyridyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1605Cm
-1
Embodiment 224
The 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also }-n-butyl acrylate (trans-isomer(ide))
1690,1620,1510Cm infrared spectra (whiteruss):
-1
Embodiment 225
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-methoxy methyl phenylpiperidines (trans-isomer(ide))
1640,1590,1510,1440,1415Cm infrared spectra (whiteruss):
-1
Embodiment 226
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and the 2-(2-methoxy ethyl) piperidines (trans-isomer(ide))
1635,1590,1510Cm infrared spectra (whiteruss):
-1
Embodiment 227
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-2-acetoxy-methyl piperidines (trans-isomer(ide))
1740,1640,1590Cm infrared spectra (trichloromethane):
-1
Embodiment 228
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-and 2-(2-acetoxyl group ethyl) piperidines (trans-isomer(ide))
1725,1635,1585,1515Cm infrared spectra (trichloromethane):
-1
Embodiment 229
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-piperidines-2-carboxylic acid (trans-isomer(ide))
3350,1750,1630,1560,1510Cm infrared spectra (whiteruss):
-1
Embodiment 230
1-(3-the 2-(3-aminophenyl) and pyrazolo (1,5-a) pyridin-3-yl) acryl-2-ethyl piperidine (trans-isomer(ide))
3410,3340,3240,1635,1605Cm infrared spectra (whiteruss):
-1
Embodiment 231
1-(3-the 2-(4-aminophenyl) pyrazolo (1,5-a) pyridin-3-yl }-acryl)-2-ethyl piperidine (trans-isomer(ide))
3335,3220,1635,1605,1580Cm infrared spectra (whiteruss):
-1
Embodiment 232
1-(3-the 2-(3-acetylamino phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3380,1685,1635Cm infrared spectra (whiteruss):
-1
Embodiment 233
1-(3-the 2-(4-acetylamino phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3250,1685,1635,1595Cm infrared spectra (whiteruss):
-1
Embodiment 234
1-(3-2-(3-methanesulfonamido phenyl) and pyrazolo (1,5-a)-pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3080,1635,1610Cm infrared spectra (whiteruss):
-1
Embodiment 235
1-(3-2-(3-methoxycarbonyl aminophenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3260,1725,1640Cm infrared spectra (whiteruss):
-1
Embodiment 236
1-(3-2-(3-methylamino phenyl) and pyrazolo (1,5-a) pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
3500,1635,1580,1510Cm infrared spectra (whiteruss):
-1
Embodiment 237
1-(3-the 2-(3-dimethylaminophenyl) and pyrazolo (1,5-a)-pyridin-3-yl } acryl)-2-ethyl piperidine (trans-isomer(ide))
Infrared spectra (whiteruss): 1640,1600Cm
-1
Embodiment 238
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-4-toluene piperidine hydrochlorate (trans-isomer(ide))
2400,1650,1580,1500Cm infrared spectra (whiteruss):
-1
The method that employing is similar to embodiment 22 makes following compound (embodiment 239 and 240).
Embodiment 239
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-3-ethyl piperidine (trans-isomer(ide))
Infrared spectra (trichloromethane): 1640,1590Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.90(3H, t, J=7.5Hz) 1.10～2.10(7H, m), 2.20～3.10(2H, m), 3.70～4.20(2H, m), and 6.68(1H, d, J=18Hz), and 6.85(1H, t, J=8.0Hz)
7.27（1H，t，J＝8.0Hz），7.30～7.54（3H，m），7.54～7.82（3H，m），7.93（1H，d，J＝18Hz），8.47（1H，d，J＝8Hz）
Embodiment 240
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-4-ethyl piperidine (trans-isomer(ide))
1635,1590,1520Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.89(3H, t, J=6.2Hz), 1.03～1.47(4H, m), 1.72(2H, d, J=11Hz), 2.78(2H, t, J=13Hz), 4.22(2H, wide), 6.60(1H, d, J=16Hz), 6.76(1H, td, J=7Hz and 1Hz), 7.06～7.67(7H, m), 7.82(1H, d, J=16Hz), 8.39(1H, d, J=7Hz)
Mass spectrum: 359(M
+)
The method that employing is similar to embodiment 62 makes following compound (embodiment 241 and embodiment 242).
Embodiment 241
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-3-ethyl piperidine (trans-isomer(ide))
Infrared spectra (trichloromethane): 1640,1590Cm
-1
Embodiment 242
1-(the 3-(2-phenylpyrazole is (1,5-a] pyridin-3-yl) acryl also)-4-ethyl piperidine (trans-isomer(ide))
1635,1590,1520Cm infrared spectra (trichloromethane):
-1
The method that employing is similar to embodiment 25 makes following compound (embodiment 243 and 244).
Embodiment 243
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-3-ethyl piperidine (trans-isomer(ide))
Infrared spectra (trichloromethane): 1640,1590Cm
-1
Embodiment 244
1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-4-ethyl piperidine (trans-isomer(ide))
1635,1590,1520Cm infrared spectra (trichloromethane):
-1
Embodiment 245
With (2R)-1-(3-(2-phenylpyrazole also (1; 5-a) acryl pyridin-3-yl))-and the 2-(2-hydroxyethyl) methylene dichloride (3 milliliters) solution of piperidines (trans-isomer(ide)) (0.50 gram) is across the glass solar light irradiation, and placed 4 hours.Subsequently solution is evaporated in a vacuum, resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of aluminium chromatographic sheet, makes eluant with the mixture of methylene dichloride and ethyl acetate (5: 1).Merge and contain purpose compound part, use dichloromethane extraction.Extract evaporates in a vacuum, obtains (2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) piperidines (cis-isomeride) (0.15 gram) oily matter.
1630,1590,1520Cm infrared spectra (trichloromethane):
-1
Nucleus magnetic resonance (CDCl
3, δ): 0.73～2.01(8H, m), 1.70(1H, S), 2.75(1H, td, J=13.5Hz and 3Hz), 3.00～4.10(3H, m), 4.52～4.81(1H, m), 6.08(1H, d, J=12Hz), 6.78(1H, td, J=7Hz and 1Hz), 6.84(1H, d, J=12Hz), 7.06～7.87(7H, m), 8.41(1H, d, J=7Hz)
Mass spectrum: 375(M
+)
Embodiment 246
The method that employing is similar to embodiment 245 obtains also (1,5-a) pyridin-3-yl of 3-(2-phenylpyrazole)-ethyl propenoate (cis-isomeride).
Fusing point: 54～55 ℃
Infrared spectra (whiteruss): 1705,1635Cm
-1
Nucleus magnetic resonance (CDCl
3, δ): 1.17(3H, t, J=7.0Hz), and 4.13(2H, q, J=7Hz), and 6.05(1H, d, J=12.0Hz), 6.50～7.97(9H, m), and 8.48(1H, dd, J=6.5Hz)
C
17H
16N
2O
2The computational analysis value:
C73.65，H5.52，N9.58
Experimental value: C74.24, H5.92, N9.49
Embodiment 247
The method that employing is similar to embodiment 8 makes also (1,5-a) pyridin-3-yl of 3-(2-phenylpyrazole) vinylformic acid (cis-isomeride)
Fusing point: 153～155 ℃
1680,1630,1600Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (CDCl
3, δ): 6.15(1H, d, J=12.0Hz), 6.70～7.92(9H, m), and 8.53(1H, dd, J=7.0Hz and 1.0Hz), 8.97～9.60(1H, m)
C
16H
12N
2O
2The computational analysis value:
C72.71，H4.58，N10.60
Experimental value: C72.87, H4.67, N10.58
Embodiment 248
With (2R)-1-(the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also) acryl)-the 2-(2-hydroxyethyl) solution of piperidines (trans-isomer(ide)) (0.50 gram) in methylene dichloride (saturated with hydrogen chloride gas) (3 milliliters) at room temperature stirs.Divided to add methylene dichloride (saturated with hydrogen chloride gas) for 4 times in 7 hours in solution, reaction mixture evaporates in a vacuum.In resistates, add tetrahydrofuran (THF) (5 milliliters) and stirring, collect the throw out that produces by filtering, drying obtains (2R)-2-(2-{ the 3-(2-phenylpyrazole is (1,5-a)-pyridin-3-yl also) acryloxy } ethyl) piperidine hydrochlorate (trans-isomer(ide)) (0.53 gram).
Fusing point: 223.5～225 ℃
1715,1705,1620,1590,1515Cm infrared spectra (whiteruss):
-1
Nucleus magnetic resonance (DMSO-d
6, δ): 1.18～3.30(10H, m), and 3.48(1H, d, J=12Hz),
4.32（2H，t，J＝6Hz），6.25（1H，d，J＝16Hz），6.87（1H，t，J＝7Hz），7.27～7.90（7H，m），7.88（1H，d，J＝16Hz），8.50（1H，d，J＝7Hz）
Mass spectrum: 375(M
+)
(α)
25.6 ° D=-7.35 ° (C=1.06, ethanol)
Embodiment 249
The method that employing is similar to embodiment 248 makes 2-(2-{ the 3-(2-phenylpyrazole is (1,5-a) pyridin-3-yl also)-acryloxy } ethyl) piperidine hydrochlorate (trans-isomer(ide))
Fusing point: 217～220 ℃
1715,1705,1620,1590,1515Cm infrared spectra (whiteruss):
-1
Claims (1)
1, a kind of preparation method who prepares following Pyrazolopyridine compound of structural formula and salt thereof:
In the formula: R
1Be low-carbon alkyl, have one or more suitable substituent aryl or heterocyclic group,
R
2Be the following group of structural formula:
(R wherein
4Be amino or the hydroxyl of having protected, R
5Be hydrogen or low-carbon alkyl);
Cyano group;
The group that structural formula is following:
-A-R
6
(R wherein
6Be acyl group, A has one or more suitable substituent low-carbon (LC) aliphatic hydrocarbon groups);
Amidation carboxyl;
Amino or protected amino;
R
3Be hydrogen, low-carbon alkyl, low-carbon alkoxy or halogen,
Comprising:
1) the following compound or its salt of structural formula
(R in the formula
1, R
3And R
5Definition as above respectively)
The compound or its salt following with structural formula
(R in the formula
4Definition as above)
React, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3, R
4And R
5Definition as above respectively)
2) make the following compound or its salt of structural formula
(R in the formula
1And R
3Definition as above respectively)
Carry out dehydration reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1And R
3Definition as above respectively)
3), make the following compound or its salt of structural formula
(R in the formula
1And R
3Define as above R respectively
7Be the lower alkanes acyl group) tie up the uncommon reaction of ladder, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3And R
6Define as above A
1Be to have one or more suitable substituent low-carbon (LC) thiazolinyls)
4). make the following compound or its salt of structural formula
(R in the formula
1, R
3Define as above R respectively with A
6 aBe the carboxyl of having protected) carry out the elimination reaction of carboxyl-protecting group, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3Define as above respectively with A)
5) make the following compound of structural formula or its reactive derivative or its salt on carboxyl
(R in the formula
1, R
3Define as above respectively with A)
React with N-replacement amine or its reactive derivative or its salt on amino, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3Define as above R respectively with A
6 bThe carboxyl that is amidation)
6), make the following compound or its salt of structural formula
(R in the formula
1, R
3And R
6Define as above A respectively
1 aBe the low-carbon (LC) thiazolinyl) carry out halogenating reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3And R
6Define as above A respectively
1 bBe the low-carbon (LC) thiazolinyl that has halogen)
7), make the following compound or its salt of structural formula
(R in the formula
1, R
3, R
6And A
1 bDefinition as above respectively)
Carry out hydrogen halide and eliminate reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3And R
6Define as above A respectively
2Be the low-carbon (LC) alkynyl)
8). make the following compound or its salt of structural formula
(R in the formula
1, R
3, R
6And A
2Definition as above respectively)
Carry out the triple bond reduction reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3, R
6And A
1 aDefinition as above respectively)
9). make the following compound of structural formula or its reactive derivative or its salt on carboxyl
(R in the formula
1, R
3Define as above respectively with A)
Carry out esterification, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3Define as above R respectively with A
3The carboxyl that is esterification)
10). make the following compound or its salt of structural formula
(R in the formula
1, R
3Define as above R respectively with A
1 NBe have hydroxyl (low-carbon (LC)) alkyl contain the N heterocyclic group)
Carry out the lower alkanes glycosylation reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3Define as above R respectively with A
2 NBe have low-carbon alkoxy (low-carbon (LC)) alkyl contain the N heterocyclic group)
11). make the following compound or its salt of structural formula
(R in the formula
1, R
3, A and R
1 NDefinition as above respectively)
Carry out acylation reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3Define as above R respectively with A
3 NBe have acyloxy (low-carbon (LC)) alkyl contain the N heterocyclic group)
12). make the following compound or its salt of structural formula
(R in the formula
1, R
3Define as above R respectively with A
4 NBe have the carboxyl protected contain the N heterocyclic group)
Carry out the elimination reaction of carboxyl-protecting group, obtain the following compound or its salt of structural formula,
R in the formula
1, R
3Define as above R respectively with A
5 NBe have a carboxyl contain the N heterocyclic group)
13). make the following compound or its salt of structural formula
(R in the formula
2And R
3Define as above R respectively
1 aBe the aryl that has nitro)
Carry out nitro-reduction reaction, obtain the following compound or its salt of structural formula,
(R in the formula
2And R
3Define as above R respectively
1 bBe to have amino aryl)
14). make the following compound or its salt of structural formula
(R in the formula
1 b, R
2And R
3Definition as above respectively)
Introduce the reaction of amido protecting group, obtain the following compound or its salt of structural formula,
(R in the formula
2And R
3Define as above R respectively
1 cBe the aryl that has the amino of having protected)
15). make the following compound or its salt of structural formula
(R in the formula
1And R
3Definition as above respectively)
The compound or its salt following with structural formula
(R in the formula
6And A
1Define as above respectively, X is a leavings group)
React, obtain the following compound or its salt of structural formula,
(R in the formula
1, R
3, R
6And A
1Definition as above respectively)
16). make the following compound of structural formula or its reactive derivative or its salt on carboxyl
(R in the formula
1And R
3Definition as above respectively)
React with N-replacement amine or its reactive derivative or its salt on amino, obtain the following compound or its salt of structural formula,
(R in the formula
1And R
3Define as above R respectively
2 aThe carboxyl that is amidation)
17). make the following compound or its salt of structural formula
(R in the formula
1And R
3Definition as above respectively)
Carry out the nitroso-group reduction reaction, obtain the following compound or its salt of structural formula,
(R in the formula
1And R
3Define as above R respectively
2 bThe amino that is amido protecting)
Or
18). make the following compound or its salt of structural formula
(R in the formula
1And R
3Definition as above respectively)
Introduce the reaction of amido protecting group, obtain the following compound or its salt of structural formula.
(R in the formula
1And R
3Define as above R respectively
2 cBe the amino of having protected)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878713908A GB8713908D0 (en) | 1987-06-15 | 1987-06-15 | Pyrazolopyridine compound |
| GB878719724A GB8719724D0 (en) | 1987-08-20 | 1987-08-20 | Pyrazolopyridine compound |
| GB8730330 | 1987-12-31 | ||
| GB8713908 | 1987-12-31 | ||
| GB878730330A GB8730330D0 (en) | 1987-12-31 | 1987-12-31 | Pyrazolopyridine compound & processes for preparation thereof |
| GB8719724 | 1987-12-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1031376A true CN1031376A (en) | 1989-03-01 |
Family
ID=27263458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88104322A Pending CN1031376A (en) | 1987-06-15 | 1988-06-14 | Pyrazolopyridine compound and preparation method thereof |
Country Status (16)
| Country | Link |
|---|---|
| US (6) | US4925849A (en) |
| EP (1) | EP0299209B1 (en) |
| JP (1) | JP2674099B2 (en) |
| KR (1) | KR890000483A (en) |
| CN (1) | CN1031376A (en) |
| AT (1) | ATE127801T1 (en) |
| AU (1) | AU615913B2 (en) |
| DE (1) | DE3854454T2 (en) |
| DK (1) | DK323688A (en) |
| ES (1) | ES2076935T3 (en) |
| FI (1) | FI882813A (en) |
| GR (1) | GR3017850T3 (en) |
| HU (1) | HU200180B (en) |
| IL (1) | IL86674A0 (en) |
| NO (1) | NO168585C (en) |
| PT (1) | PT87700B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100342842C (en) * | 1999-11-19 | 2007-10-17 | 莱雅公司 | Composition for dyeing keratnous fibres containing 3-amino pyrazolo-[1,5-A]-pyridines, dyeing method, novel 3-amino pyrazolo-[1,5-A]-pyridines |
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| US4925849A (en) * | 1987-06-15 | 1990-05-15 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutically useful pyrazolopyridines |
| US5338743A (en) * | 1988-06-06 | 1994-08-16 | Fujisawa Pharmaceutical Co., Ltd. | New use of the adenosine antagonist |
| GB8901423D0 (en) * | 1989-01-23 | 1989-03-15 | Fujisawa Pharmaceutical Co | Pyrazolopyridine compound and processes for preparation thereof |
| DE3942357A1 (en) * | 1989-12-21 | 1991-06-27 | Boehringer Mannheim Gmbh | 3-AMINOPYRAZOLO-HETEROCYCLES, THEIR USES FOR THE DETERMINATION OF HYDROGEN PEROXIDE, HYDROGEN PEROXIDE-FORMING SYSTEMS, PEROXIDASE, PEROXIDATIALLY ACTIVE SUBSTANCES OR OF ELECTRONIC AROMATIC COMPOUNDS, CORRESPONDING PROCEDURES AND COMPOUNDS THEREOF |
| GB9015764D0 (en) * | 1990-07-18 | 1990-09-05 | Fujisawa Pharmaceutical Co | Pyrazolopyridine compound and processes for preparation thereof |
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| GB9107513D0 (en) * | 1991-04-10 | 1991-05-29 | Fujisawa Pharmaceutical Co | Pyrazolopyridine compound and processes for preparation thereof |
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| BR9809288A (en) * | 1997-04-22 | 2001-08-07 | Cocensys Inc | Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and their use |
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| DE69919887T2 (en) | 1998-11-03 | 2005-09-15 | Glaxo Group Ltd., Greenford | PYRAZOLOPYRIDINE DERIVATIVE AS SELECTIVE COX-2 INHIBITORS |
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| CA2654498A1 (en) | 2006-06-06 | 2007-12-21 | Avigen, Inc. | Substituted pyrazolo[1,5-.alpha.]pyridine compounds and their methods of use |
| EP1939180A1 (en) * | 2006-12-20 | 2008-07-02 | sanofi-aventis | Heteroarylacrylamides and their use as pharmaceuticals for the stimulation of the expression of endothelial NO synthase |
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| CA2721670C (en) * | 2008-04-15 | 2013-09-10 | Eisai R&D Management Co., Ltd. | 3-phenylpyrazolo[5,1-b]thiazole compound |
| WO2010021681A2 (en) * | 2008-08-18 | 2010-02-25 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
| EP2177218A1 (en) | 2008-10-15 | 2010-04-21 | Medizinische Universität Wien | Regenerative therapy |
| WO2011043387A1 (en) * | 2009-10-08 | 2011-04-14 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Pyrazoloxazole compound |
| AR078521A1 (en) * | 2009-10-08 | 2011-11-16 | Eisai R&D Man Co Ltd | PIRAZOLOTIAZOL COMPOUND |
| KR20200127273A (en) | 2012-04-26 | 2020-11-10 | 브리스톨-마이어스 스큅 컴퍼니 | Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CA2871637A1 (en) | 2012-04-26 | 2013-10-31 | Bristol-Myers Squibb Company | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| JP6101343B2 (en) | 2012-04-26 | 2017-03-22 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Imidazothiadiazole and imidazopyridazine derivatives as protease-activated receptor 4 (PAR4) inhibitors for the treatment of platelet aggregation |
| US9617279B1 (en) | 2014-06-24 | 2017-04-11 | Bristol-Myers Squibb Company | Imidazooxadiazole compounds |
| US9598419B1 (en) | 2014-06-24 | 2017-03-21 | Universite De Montreal | Imidazotriazine and imidazodiazine compounds |
| US11970499B1 (en) | 2023-12-22 | 2024-04-30 | King Faisal University | Pyrazolo[1,5-c]pyrimidine compounds as CK2 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5229318B2 (en) * | 1972-03-30 | 1977-08-01 | ||
| US4017597A (en) * | 1974-10-30 | 1977-04-12 | Monsanto Company | Unitized solid phase immunoassay kit and method |
| JPS5154583A (en) * | 1974-11-01 | 1976-05-13 | Kyorin Seiyaku Kk | Shinkipirazoro * 1 55a * pirijinjudotaino seizoho |
| US4097483A (en) * | 1974-11-01 | 1978-06-27 | Kyorin Pharmaceutical Co., Ltd. | Pyrazolo 1,5-a!pyridines |
| DK275083A (en) * | 1982-06-16 | 1983-12-17 | May & Baker Ltd | PROCEDURE FOR PREPARING A PYRAZOLOPYRIDINE DERIVATIVE |
| JPS60248689A (en) * | 1984-05-24 | 1985-12-09 | Mitsubishi Paper Mills Ltd | 3-(3'-pyrazolo(1,5-a)pyridyl)acrolein derivative |
| US4925849A (en) * | 1987-06-15 | 1990-05-15 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutically useful pyrazolopyridines |
-
1988
- 1988-06-06 US US07/202,526 patent/US4925849A/en not_active Expired - Fee Related
- 1988-06-09 PT PT87700A patent/PT87700B/en not_active IP Right Cessation
- 1988-06-09 IL IL86674A patent/IL86674A0/en unknown
- 1988-06-10 AU AU17602/88A patent/AU615913B2/en not_active Ceased
- 1988-06-11 EP EP88109331A patent/EP0299209B1/en not_active Expired - Lifetime
- 1988-06-11 AT AT88109331T patent/ATE127801T1/en not_active IP Right Cessation
- 1988-06-11 ES ES88109331T patent/ES2076935T3/en not_active Expired - Lifetime
- 1988-06-11 DE DE3854454T patent/DE3854454T2/en not_active Expired - Fee Related
- 1988-06-13 FI FI882813A patent/FI882813A/en not_active Application Discontinuation
- 1988-06-14 HU HU883046A patent/HU200180B/en not_active IP Right Cessation
- 1988-06-14 CN CN88104322A patent/CN1031376A/en active Pending
- 1988-06-14 KR KR1019880007185A patent/KR890000483A/en not_active Application Discontinuation
- 1988-06-14 JP JP63146080A patent/JP2674099B2/en not_active Expired - Lifetime
- 1988-06-14 DK DK323688A patent/DK323688A/en not_active Application Discontinuation
- 1988-06-14 NO NO882608A patent/NO168585C/en unknown
-
1989
- 1989-09-15 US US07/407,747 patent/US4994453A/en not_active Expired - Fee Related
-
1990
- 1990-03-12 US US07/492,486 patent/US5087629A/en not_active Expired - Fee Related
- 1990-03-19 US US07/495,799 patent/US5102878A/en not_active Expired - Fee Related
- 1990-06-19 US US07/540,325 patent/US5102869A/en not_active Expired - Fee Related
-
1992
- 1992-10-30 US US07/968,664 patent/US5296490A/en not_active Expired - Fee Related
-
1995
- 1995-10-25 GR GR950402954T patent/GR3017850T3/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100342842C (en) * | 1999-11-19 | 2007-10-17 | 莱雅公司 | Composition for dyeing keratnous fibres containing 3-amino pyrazolo-[1,5-A]-pyridines, dyeing method, novel 3-amino pyrazolo-[1,5-A]-pyridines |
Also Published As
| Publication number | Publication date |
|---|---|
| IL86674A0 (en) | 1988-11-30 |
| US4925849A (en) | 1990-05-15 |
| DK323688A (en) | 1988-12-16 |
| GR3017850T3 (en) | 1996-01-31 |
| HU200180B (en) | 1990-04-28 |
| NO168585C (en) | 1992-03-11 |
| US5087629A (en) | 1992-02-11 |
| EP0299209A3 (en) | 1990-05-09 |
| ES2076935T3 (en) | 1995-11-16 |
| ATE127801T1 (en) | 1995-09-15 |
| EP0299209A2 (en) | 1989-01-18 |
| EP0299209B1 (en) | 1995-09-13 |
| JPS6445385A (en) | 1989-02-17 |
| US4994453A (en) | 1991-02-19 |
| US5102869A (en) | 1992-04-07 |
| FI882813A (en) | 1988-12-16 |
| NO882608D0 (en) | 1988-06-14 |
| AU1760288A (en) | 1988-12-15 |
| AU615913B2 (en) | 1991-10-17 |
| DE3854454D1 (en) | 1995-10-19 |
| KR890000483A (en) | 1989-03-14 |
| US5296490A (en) | 1994-03-22 |
| US5102878A (en) | 1992-04-07 |
| NO882608L (en) | 1988-12-16 |
| HUT47110A (en) | 1989-01-30 |
| PT87700A (en) | 1988-07-01 |
| PT87700B (en) | 1992-10-30 |
| JP2674099B2 (en) | 1997-11-05 |
| NO168585B (en) | 1991-12-02 |
| DE3854454T2 (en) | 1996-02-15 |
| DK323688D0 (en) | 1988-06-14 |
| FI882813A0 (en) | 1988-06-13 |
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| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |